Tetrahydropyran and thiopyran derivatives having multimodal activity against pain
10807970 ยท 2020-10-20
Assignee
Inventors
- Monica GARCIA-LOPEZ (Barcelona, ES)
- Carmen Almansa-Rosales (Barcelona, ES)
- Ana Virginia Llorente-Fernandez (Barcelona, ES)
- Ute Christmann (Barcelona, ES)
- Sergio Rodriguez Escrich (Barcelona, ES)
Cpc classification
C07D307/04
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07D407/06
CHEMISTRY; METALLURGY
International classification
C07D405/04
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07D307/04
CHEMISTRY; METALLURGY
C07D407/06
CHEMISTRY; METALLURGY
Abstract
The present invention relates to tetrahydropyran and thiopyran derivatives having dual pharmacological activity towards both the sigma () receptor, and the -opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
Claims
1. Compound of Formula (I): ##STR00666## wherein R.sub.1 is ##STR00667## m is 1, 2 or 3; n is 0, 1 or 2; p is 0, 1 or 2; q is 0 or 1; W is nitrogen or carbon; X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from the group consisting of halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; Y is S or O; R.sub.1 is selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein the cycloalkyl, aryl or heterocyclyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11; additionally, the cycloalkyl or non-aromatic heterocyclyl in R.sub.1, if substituted, may also be substituted with ##STR00668## or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from the group consisting of OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.2 is selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein the cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, the cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with ##STR00669## or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from the group consisting of OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; R.sub.3 and R.sub.3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.4 and R.sub.4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl, alternatively, R.sub.4 and R.sub.4, together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; R.sub.4 and R.sub.4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl, alternatively, R.sub.4 and R.sub.4, together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; R.sub.5 and R.sub.5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.6 and R.sub.6 are independently selected from the group consisting of hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; and wherein ##STR00670## is selected from the group consisting of ##STR00671## wherein R.sub.n is selected from the group consisting of unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from the group consisting of OR.sub.13, halogen, CN, haloalkyl, haloalkoxy, SR.sub.13, S(O)R.sub.13, and S(O).sub.2R.sub.13; wherein R.sub.13, and R.sub.13 are independently selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl; the aryl, heterocyclyl or cycloalkyl other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, R.sub.14, OR.sub.14, NO.sub.2, NR.sub.14R.sub.14, NR.sub.14C(O)R.sub.14, NR.sub.14S(O).sub.2R.sub.14, S(O).sub.2NR.sub.14R.sub.14, NR.sub.14C(O)NR.sub.14R.sub.14, SR.sub.14, S(O)R.sub.14, S(O).sub.2R.sub.14, CN, haloalkyl, haloalkoxy, C(O)OR.sub.14, C(O)NR.sub.14R.sub.14, OCH.sub.2CH.sub.2OH, NR.sub.14S(O).sub.2NR.sub.14R.sub.14 and C(CH.sub.3).sub.2OR.sub.14; additionally, wherein the cycloalkyl or non-aromatic heterocyclyl, other than those defined in R.sub.1 or R.sub.2, if substituted, may also be substituted with ##STR00672## or O; wherein R.sub.14, R.sub.14 and R.sub.14 are independently selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and wherein R.sub.14 is selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc; optionally as a stereoisomer, including enantiomers and diastereomers, a racemate or as a mixture of at two of stereoisomers, including enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof; wherein the following compound is excluded: ##STR00673## and the following compound is excluded: ##STR00674##
2. The compound according to claim 1, wherein ##STR00675## is ##STR00676## and W is nitrogen or carbon.
3. The compound according to claim 2, wherein W is nitrogen.
4. The compound according to claim 1, wherein X is a bond or O.
5. The compound according to claim 4, wherein X is a bond.
6. The compound according to claim 1, wherein R.sub.1 is selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl.
7. The compound according to claim 6, wherein R.sub.1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted vinyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl and substituted or unsubstituted pyridine.
8. The compound according to claim 1, wherein R.sub.2 is selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl.
9. The compound according to claim 8, wherein R.sub.2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted 2-methylprop-1-enyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted isobutyl, CH.sub.2C(CH.sub.3).sub.2F, CH.sub.2C(CH.sub.3).sub.2OH, substituted or unsubstituted phenyl or substituted or unsubstituted pyridine.
10. The compound according to claim 1, wherein R.sub.3 and R.sub.3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl.
11. The compound according to claim 10, wherein R.sub.3 is substituted or unsubstituted methyl.
12. The compound according to claim 1, wherein R.sub.4 and R.sub.4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl and/or R.sub.4 and R.sub.4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl.
13. The compound according to claim 12, wherein R.sub.4 and R.sub.4 are both hydrogen or substituted or unsubstituted methyl; and/or R.sub.4 and R.sub.4 are both hydrogen or substituted or unsubstituted methyl.
14. The compound according to claim 1, wherein R.sub.4 and R.sub.4, together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl.
15. The compound according to claim 14, wherein R.sub.4 and R.sub.4, together with the carbon atom to which they are attached, form a substituted or unsubstituted cyclopentyl.
16. The compound according to claim 1, wherein R.sub.5 and R.sub.5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8.
17. The compound according to claim 16, wherein R.sub.5 and R.sub.5 are selected from the group consisting of hydrogen or substituted or unsubstituted methyl.
18. The compound according to claim 1, wherein the compound is selected from the group consisting of: (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (S)-(4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9-yl)(phenyl)methanone, (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9-yl)(pyridin-2-yl)methanone, (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone, (9-(4-isobutylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9-yl)(phenyl)methanone, (4-(4-benzylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(phenyl)methanone, (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-3-yl)methanone, (4-(4-isobutylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(phenyl)methanone, (4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(phenyl)methanone, (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(phenyl)methanone, (4-(4-isobutylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone, (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone, (4-(4-benzylpiperazin-1-yl)-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(3-(benzyl(methyl)amino)azetidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (3-(4-benzylpiperazin-1-yl)tetrahydrofuran-3-yl)(pyridin-2-yl)methanone, (4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(3-((2-isopropoxyethyl)(methyl)amino)azetidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-benzyl-1,4-diazepan-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 2-methyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2S,4R)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2R,4S)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-benzyl-4-(9-ethyl-6-oxaspiro[4.5]decan-9-yl)piperazine, 1-benzyl-4-(4-phenyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-(4-ethyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine, 1-isobutyl-4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine, 1-benzyl-4-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)piperazine, 1-benzyl-4-(2,2-dimethyl-4-phenyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2-isopropoxyethyl)-4-(2,2,4-trimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-isopropoxyethyl)piperazine, 1-benzyl-4-(4-benzyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,2-dimethyl-4-propyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-benzyl-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(4-cyclopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(2,2-dimethyl-4-vinyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 2-(2,2-dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)ethanol, 1-(4-(2-Methoxyethyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, (2,2-dimethyl-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (9-(4-isobutylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9-yl)(pyridin-2-yl)methanone, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-phenethyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4-yl)piperazine, (2,2-dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-(3-fluoropyridin-2-yl)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-(3-chloropyridin-2-yl)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-(3-chloropyridin-4-yl)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-dimethyl-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-dimethyl-4-(4-(pyridin-4-ylmethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(4-fluorobenzyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(3-fluorobenzyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-dimethyl-4-(4-(1-phenylethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-isopentylpiperazin-1-yl)-2,2-dimethyl tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyl tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-ethoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-methoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-dimethyl-4-(4-(2-(2,2,2-trifluoroethoxy)ethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-(2-hydroxy-2-methyl propoxy)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(3-isopropoxypropyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(5-(2-isopropoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (3-(4-(2-isopropoxyethyl)piperazin-1-yl)tetrahydrofuran-3-yl)(pyridin-2-yl)methanone, 2-(4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine, (4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, 1-isopentyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4-yl)piperazine, (2,2-dimethyl-4-(4-(2-(pyridin-3-yl)ethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-dimethyl-4-(4-(2-(pyridin-4-yl)ethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-4-yl)ethyl)piperazine, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-3-yl)ethyl)piperazine, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-(3-fluoropyridin-4-yl)ethyl)piperazine, (4-(4-(2-(3-fluoropyridin-4-yl)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-isopentyl-1,4-diazepan-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-2-yl)ethyl)piperazine, (4-(4-(2-isopropoxyethyl)-1,4-diazepan-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(2-fluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, (4-(4-(3-hydroxy-3-methylbutyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(3-fluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,5-difluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(3-fluorophenethyl)piperazine, 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-fluorophenethyl)piperazine, (2R,4S)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2S,4R)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2R,4S)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2S,4R)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(2,5-difluorophenethyl)-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,3-difluorophenethyl)-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,3-difluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperazine, (4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(3-ethoxypropyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(2-ethoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(2-isobutoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(3-isopropoxypropyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(3-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(4-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(2-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-fluorophenethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (S)-1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, (R) 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, (S)-(4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-(2-fluoro-2-methylpropoxy)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(3-fluoro-3-methylbutyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (2,2-Dimethyl-4-(4-(3-methylbut-3-enyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-3-ylmethyl)piperazine, 1-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-2-ylmethyl)piperazine, 3-((4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazin-1-yl)methyl)benzonitrile, 1-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-3-ylmethyl)piperazine, 1-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)-4-isobutylpiperazine, 2-(4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)pyridine, 2-(4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine, 2-(4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)pyridine, (2,2-dimethyl-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2-cyclopropylethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanol, (4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanol, (4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanol, (S)-(4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (S)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (S)-(4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((S)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((R)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R) 4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (S) 4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((R)-4-((R)-3-((2-isopropoxyethyl)(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((S)-4-((R)-3-((2-isopropoxyethyl)(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((R)-4-((S)-3-((2-isopropoxyethyl)(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((S)-4-((S)-3-((2-isopropoxyethyl)(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyl tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((S)-4-((R)-3-(isopentyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((R)-4-((R)-3-(isopentyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyl tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((R)-4-((S)-3-(isopentyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((S)-4-((S)-3-(isopentyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(1-benzylpiperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(1-benzylpiperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2R,4R)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2S,4S)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-Benzyl-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-((2S,4S)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-(2-isopropoxyethyl)piperazine, 1-((2S,4R)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-(2-isopropoxyethyl)piperazine, 1-((2S,4S)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, 1-((2S,4R)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, 1-((2S,4S)-2,4-dimethyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, 1-((2S,4R)-2,4-dimethyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, 1-benzyl-4-((2S,4S)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-((2S,4R)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-benzyl-4-(4-methyltetrahydro-2H-pyran-4-yl)piperidine, 1-benzyl-4-(4-ethyltetrahydro-2H-pyran-4-yl)piperidine, 1-Benzyl-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidine, 4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-(2-fluorophenethyl)piperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(1-isopentylpiperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-phenethylpiperidine, 4-((4-(4-ethyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(4-fluorobenzyl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-isopropoxyethyl)piperazine, (4-(4-isopentylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-isopentyl-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 4-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-isopentylpiperazine, (4-(4-(4-fluorobenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(4-fluorobenzyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 4-((4-(4-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 1-(2-isopropoxyethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, (4-(4-(2-isopropoxyethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-((4-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 4-((4-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 2-fluoro-5-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, ((2R,4R)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2S,4S)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-((4-(4-cyclopropyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 2-fluoro-4-((4-(4-picolinoyltetrahydro-2-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, 3-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile, pyridin-2-yl(4-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)methanone, (4-(4-(4-methoxybenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(3-fluoro-4-methoxybenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(3,4-difluorobenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(4-fluoro-3-methoxybenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(4-(2,4-difluorobenzyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)picolinonitrile, pyridin-2-yl(4-(4-((2-(trifluoromethyl)pyridin-4-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)methanone, 4-(4-((2-methoxypyridin-4-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 5-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)picolinonitrile, pyridin-2-yl(4-(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)methanone, (4-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-((1-phenyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-(1-(4-fluorobenzyl)piperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-((4-(4-picolinoyltetrahydro-2H-pyran-4-yl)piperidin-1-yl)methyl)benzonitrile, (4-(1-isopentylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (4-(1-(2-isopropoxyethyl)piperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 1-(4-fluorobenzyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperidine, 4-((4-(4-methyltetrahydro-2H-pyran-4-yl)piperidin-1-yl)methyl)benzonitrile, 1-isopentyl-4-(4-methyltetrahydro-2H-pyran-4-yl)piperidine, 1-(2-isopropoxyethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperidine, 4-(4-ethyltetrahydro-2H-pyran-4-yl)-1-(4-fluorobenzyl)piperidine, 4-((4-(4-ethyltetrahydro-2H-pyran-4-yl)piperidin-1-yl)methyl)benzonitrile, 4-(4-ethyltetrahydro-2H-pyran-4-yl)-1-isopentylpiperidine, 4-(4-ethyltetrahydro-2H-pyran-4-yl)-1-(2-isopropoxyethyl)piperidine, 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(3-fluorophenethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2-fluorophenethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,5-difluorophenethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,3-difluorophenethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 3-(2-(4-(4-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethyl)benzonitrile, 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-4-yl)ethyl)piperazine, 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-3-yl)ethyl)piperazine, 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-2-yl)ethyl)piperazine, 1-(2-(3-fluoropyridin-4-yl)ethyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(3-fluorophenethyl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-fluorophenethyl)piperazine, 1-(2,5-difluorophenethyl)-4-(4-ethyltetrahydro-2H-pyran-4-yl)piperazine, 1-(2,3-difluorophenethyl)-4-(4-ethyltetrahydro-2H-pyran-4-yl)piperazine, 3-(2-(4-(4-ethyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethyl)benzonitrile, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-4-yl)ethyl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-3-yl)ethyl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-(pyridin-2-yl)ethyl)piperazine, 1-(4-ethyltetrahydro-2H-pyran-4-yl)-4-(2-(3-fluoropyridin-4-yl)ethyl)piperazine, ((2R,4R)-2-methyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2S,4S)-2-methyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(3-(4-(2-isopropoxyethyl)piperazin-1-yl)tetrahydrofuran-3-yl)(pyridin-2-yl)methanone, (S)-(3-(4-(2-isopropoxyethyl)piperazin-1-yl)tetrahydrofuran-3-yl)(pyridin-2-yl)methanone, (S)-(4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, (R)-(4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2R,4R)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2S,4S)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2S,4R)-4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, ((2R,4S)-4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone, 4-((4-((2S,4R)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile and 4-((4-((2R,4S)-4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)benzonitrile.
19. A process for the preparation of the compound of Formula (I) according to claim 1, wherein a) when R.sub.1 is C(O)R.sub.1, said process comprises treating a compound of Formula IIb ##STR00677## with a lithium salt generated from compounds of general formula IIIa
ZR.sub.1 IIIa with nBuLi, and hydrolysing the obtained imine intermediate compound to a ketone compound of formula I in the presence of an aqueous inorganic acid, or b) when R.sub.1 is C(R.sub.6R.sub.6).sub.pR.sub.1, said process comprises the reaction of compounds of general formula IIIb ##STR00678## with Grignard reagents of formula IIIb
ZMgR.sub.1 IIIb, or c) said process comprises reacting a compound of general formula VII ##STR00679## with a compound of general formula VIIIa through an alkylation reaction in the presence of an inorganic or organic base ##STR00680## or with a compound of general formula VIIIb through a reductive amination reaction in the presence of a reductive agent ##STR00681## or with a compound of general formula VIII through a condensation reaction ##STR00682## or d) when W is carbon, said process comprises the reductive alkylation of a cyano derivatives of formula V ##STR00683## with a compound of formula VIb ##STR00684## in the presence of lithium naphthalenide, wherein R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X, Y and W are as defined in claim 17, L is a leaving group, including halogen, mesylate, tosylate and triflate, Z is chloro or bromo, M is ##STR00685## and PG is a protecting group.
20. A process for the preparation of the compound of Formula (I) according to claim 1, employing a compound of Formula IIa, IIb, IIIa, IIIIb, IV, V, VIa, VIb, VII, VIIIa, VIIIb or VIIIc, ##STR00686## and/or a compound of Formula V, IX, Xa or Xb, ##STR00687## wherein R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, m, n, p, q, X, Y and W are as defined in claim 17, L is a leaving group, including halogen, mesylate, tosylate and triflate, Z is chloro or bromo, M is ##STR00688## and PG is a protecting group.
21. A pharmaceutical composition which comprises the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
22. A method of treating pain in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1.
23. The method according to claim 22, wherein the pain is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia and hyperalgesia.
24. A process for the preparation of the compound of Formula (I) according to claim 1, wherein said compound of Formula (I) is made from intermediate (IIa) ##STR00689## obtained from the reaction of a compound of formula V ##STR00690## with a compound of formula VIa ##STR00691## in the presence of a base or wherein said compound of Formula (I) is made from intermediate (IIb) ##STR00692## obtained from the reaction of a compound of formula V ##STR00693## with a compound of formula VIb ##STR00694## in the presence of a base, or wherein said compound of Formula (I) is made from intermediate (IIa) ##STR00695## obtained from the reaction of a compound of formula IX ##STR00696## with a compound of formula Xa ##STR00697## in the presence of a base, or wherein said compound of Formula (I) is made from intermediate (IIb) ##STR00698## obtained from the reaction of a compound of formula IX ##STR00699## with a compound of formula Xb ##STR00700## in the presence of a base, wherein M is ##STR00701## R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in claim 17, L is a leaving group, including halogen, mesylate, tosylate and triflate, Z is chloro or bromo, and PG is a protecting group.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) The invention is directed to a family of structurally distinct tetrahydropyran and thiopyran derivatives which have a dual pharmacological activity towards both the sigma () receptor and the -opioid receptor, thus solving the above problem of identifying alternative or improved pain treatments by offering such dual compounds.
(2) The invention is directed to compounds having a dual activity binding to the .sub.1 receptor and the -opioid receptor for use in the treatment of pain.
(3) As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the .sub.1 receptor and the -opioid receptor it is a preferred embodiment if the compound has a binding expressed as K.sub.i which is preferably <1000 nM for both receptors, more preferably <500 nM, even more preferably <100 nM.
(4) The applicant has surprisingly found that the problem of providing a new effective and alternative for treating pain and pain related disorders can be solved by using a multimodal balanced analgesic approach combining two different synergistic activities in a single drug (i.e., dual ligands which are bifunctional and bind to -opioid receptor and to .sub.1 receptor), thereby enhancing the opioid analgesia through the .sub.1 activation without increasing the undesirable side effects. This supports the therapeutic value of a dual MOR/.sub.1 receptor compound whereby the .sub.1 receptor binding component acts as an intrinsic adjuvant of the MOR binding component.
(5) This solution offered the advantage that the two mechanisms complement each other in order to treat pain and chronic pain using lower and better tolerated doses needed based on the potentiation of analgesia but avoiding the adverse events of -opioid receptor agonists.
(6) A dual compound that possess binding to both the -opioid receptor and to the .sub.1 receptor shows a highly valuable therapeutic potential by achieving an outstanding analgesia (enhanced in respect to the potency of the opioid component alone) with a reduced side-effect profile (safety margin increased compared to that of the opioid component alone) versus existing opioid therapies.
(7) Advantageously, the dual compounds according to the present invention would in addition show one or more the following functionalities: .sub.1 receptor antagonism and -opioid receptor agonism. It has to be noted, though, that both functionalities antagonism and agonism are also sub-divided in their effect into subfunctionalities like partial agonism or inverse agonism.
(8) Accordingly, the functionalities of the dual compound should be considered within a relatively broad bandwidth.
(9) An antagonist on one of the named receptors blocks or dampens agonist-mediated responses. Known subfunctionalities are neutral antagonists or inverse agonists.
(10) An agonist on one of the named receptors increases the activity of the receptor above its basal level. Known subfunctionalities are full agonists, or partial agonists.
(11) In addition, the two mechanisms complement each other since MOR agonists are only marginally effective in the treatment of neuropathic pain, while .sub.1 receptor antagonists show outstanding effects in preclinical neuropathic pain models. Thus, the .sub.1 receptor component adds unique analgesic actions in opioid-resistant pain. Finally, the dual approach has clear advantages over MOR agonists in the treatment of chronic pain as lower and better tolerated doses would be needed based on the potentiation of analgesia but not of the adverse events of MOR agonists.
(12) A further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients.
(13) Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies. It is also seen as a way of improving the R&D output obtained using the one drug-one target approach, which has been questioned over the last years [Bornot A, Bauer U, Brown A, Firth M, Hellawell C, Engkvist O. Systematic Exploration of Dual-Acting Modulators from a Combined Medicinal Chemistry and Biology Perspective. J. Med. Chem, 56, 1197-1210 (2013)].
(14) In its broader aspect, the present invention is directed to compounds of general Formula (I):
(15) ##STR00004##
wherein
R.sub.1 is
(16) ##STR00005##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
R.sub.2 is selected from, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
and wherein
(17) ##STR00006##
is selected from
(18) ##STR00007##
wherein R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl.
(19) In one embodiment, the present invention is directed to compounds of general Formula (I-a):
(20) ##STR00008##
wherein
R.sub.1 is
(21) ##STR00009##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
R.sub.2 is selected from, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
and wherein
(22) ##STR00010##
is selected from
(23) ##STR00011##
wherein R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl.
(24) In one embodiment, the present invention is directed to compounds of general Formula (I-b):
(25) ##STR00012##
wherein
R.sub.1 is
(26) ##STR00013##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
R.sub.2 is selected from, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
and wherein
(27) ##STR00014##
is selected from
(28) ##STR00015##
wherein R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl.
(29) These compounds above according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(30) In another embodiment, these compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.
(31) In a further embodiment the following proviso applies:
(32) R.sub.1 is not CH.sub.2NH.sub.2.
(33) In a further embodiment the following proviso applies:
(34) R.sub.1 is not CN.
(35) In a further embodiment the following compound is excluded:
(36) ##STR00016##
(37) In a further embodiment the following compound is excluded:
(38) ##STR00017##
(39) In one further embodiment W is N or CH.
(40) In one further embodiment W is N.
(41) In one further embodiment W is CH.
(42) In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I)
(43) ##STR00018##
wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, m, n and q are as defined in the description.
(44) In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I.sup.2)
(45) ##STR00019##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, m, n and q are as defined in the description.
(46) In a further embodiment, for compounds of general Formula (I) described above in which
(47) ##STR00020##
the compounds are thus compounds of general Formula (I.sup.3)
(48) ##STR00021##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m, n and q are as defined in the description;
preferably, the compounds of general Formula (I.sup.3) are compounds of general Formula (I.sup.4)
(49) ##STR00022##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m and q are as defined in the description.
preferably, the compounds of general Formula (I.sup.4) are compounds of general Formula (I.sup.4b)
(50) ##STR00023##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, X, W and m are as defined in the description.
(51) In a further embodiment, for compounds of general Formula (I) described above in which
(52) ##STR00024##
the compounds are thus compounds of general Formula (I.sup.5)
(53) ##STR00025##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.n, X, Y, W, m, n and q are as defined in the description; preferably, the compounds of general Formula (I.sup.5) are compounds of general Formula (I.sup.6)
(54) ##STR00026##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m and q are as defined in the description;
(55) In a further embodiment, for compounds of general Formula (I) described above in which
(56) ##STR00027##
the compounds are thus compounds of general Formula (I.sup.7)
(57) ##STR00028##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.n, X, Y, W, m, n and q are as defined in the description,
preferably, the compounds of general Formula (I.sup.7) are compounds of general Formula (I.sup.8)
(58) ##STR00029##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.n, X, Y, W, m and q are as defined in the description.
(59) In a further embodiment, for compounds of general Formula (I) described above in which
(60) ##STR00030##
is
(61) ##STR00031##
the compounds are thus compounds of general Formula (I.sup.9)
(62) ##STR00032##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m, n and q are as defined in the description;
preferably, the compounds of general Formula (I.sup.9) are compounds of general Formula (I.sup.10)
(63) ##STR00033##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m and q are as defined in the description.
(64) In a further embodiment, for compounds of general Formula (I) described above in which
(65) ##STR00034##
is
(66) ##STR00035##
the compounds are thus compounds of general Formula (I.sup.11)
(67) ##STR00036##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m, n and q are as defined in the description;
preferably, the compounds of general Formula (I.sup.11) are compounds of general Formula (I.sup.12)
(68) ##STR00037##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W, m and q are as defined in the description.
(69) For clarity purposes, reference is also made to the following statements below in the definitions of substitutions on alkyl etc. or aryl etc. that wherein when different radicals R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are present simultaneously in Formula I they may be identical or different. This statement is reflected in the below general Formula (I.sup.4a) being derived from and falling into general Formula (I.sup.4) as well as Formula (I).
(70) ##STR00038##
wherein R.sub.1, R.sub.2, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, X, Y, W and q are as defined in the description. In addition, m (being 0 or 1), R.sub.5 and R.sub.5 are added. As said above, this statement is thus reflected in that R.sub.5 and R.sub.5 are or could be different from R.sub.5 and R.sub.5 or not andaccordinglym being 0 or 1 is naturally resulting from m (in general Formulas (I) or (I.sup.4) being 1 or 2).
(71) The same would be applicable mutatis mutandis for general Formulas like general Formula (I) as well as the other general Formulas (I) to (I.sup.12) above.
(72) For clarity purposes, all groups and definitions described in the description and referring to compounds of general Formula (I), also apply to compounds of general Formula (I-a), (I-b), (I), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11) or (I.sup.12), (I.sup.4a) and (I.sup.4b) and to all synthesis intermediates when those groups are present in the mentioned general Markush formulae, since compounds of general Formula (I-a), (I-b), (I), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11), (I.sup.12), (I.sup.4a) or (I.sup.4b) are included in the general Formula (I).
(73) For clarity purposes, all compounds described in the description and referring to compounds of general Formula (I), (I), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.1), (I.sup.11) or (I.sup.12), and to all synthesis intermediates having the moiety (Q)
(74) ##STR00039##
can also refer to compounds exhibiting stereochemistry like (Q1) or (Q2)
(75) ##STR00040##
(76) For clarity purposes, the general Markush Formula (I)
(77) ##STR00041##
is equivalent to
(78) ##STR00042##
wherein only C(R.sub.5R.sub.5) and C(R.sub.3R.sub.3) are included into the brackets and m or n mean the number of times that C(R.sub.5R.sub.5) or C(R.sub.3R.sub.3) is repeated, respectively. The same would apply to general Markush Formulae (I), (I-a), (I-b), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.4a), (I.sup.4b), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11) or (I.sup.12) and to all synthesis intermediates when applicable. Thus in general, (where applicable) m and n mean in all general Markush Formulae (I), (I), (I-a), (I-b), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.4a), (I.sup.4b) (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11) or (I.sup.12) and to all synthesis intermediates when applicable the number of times that C(R.sub.5R.sub.5) or C(R.sub.3R.sub.3) is repeated, respectively.
(79) In addition, and for clarity purposes, it should further be understood that naturally if n is 0, R.sub.2 is still present in general Markush Formulae (I), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.4a), (I.sup.4b), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11) or (I.sup.12).
(80) Another additional embodiment of the invention relates to the compounds
(81) ##STR00043##
(4-(4-((1-phenyl-1H-pyrazol-3-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone; Compound 206) and
(82) ##STR00044##
(4-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone; Compound 207).
(83) These Compounds 206 and 207 according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof.
(84) In the context of this invention, alkyl is understood as meaning saturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses e.g. CH.sub.3 and CH.sub.2CH.sub.3. In these radicals, C.sub.1-2-alkyl represents C1- or C2-alkyl, C.sub.1-3-alkyl represents C1-, C2- or C3-alkyl, C.sub.1-4-alkyl represents C1-, C2-, C3- or C4-alkyl, C.sub.1-5-alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl, C.sub.1-6-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, C.sub.1-7-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C.sub.1-8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl, C.sub.1-10-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C.sub.1-18-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, if substituted also CHF.sub.2, CF.sub.3 or CH.sub.2OH etc. Preferably alkyl is understood in the context of this invention as C.sub.1-8alkyl like methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; preferably is C.sub.1-6alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more preferably is C.sub.1-4alkyl like methyl, ethyl, propyl or butyl.
(85) Alkenyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. CHCHCH.sub.3. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C.sub.2-10-alkenyl or C.sub.2-8-alkenyl like ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene; or is C.sub.2-6-alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C.sub.2-4-alkenyl, like ethylene, propylene, or butylenes.
(86) Alkynyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. CCH.sub.3 (1-propinyl). Preferably alkynyl in the context of this invention is C.sub.2-10-alkynyl or C.sub.2-8-alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, or octyne; or is C.sub.2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C.sub.2-4-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne.
(87) In connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkylunless defined otherwisethe term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen (F, Cl, Br, I), NR.sub.cR.sub.c, SR.sub.c, S(O)R.sub.c, S(O).sub.2R.sub.c, OR.sub.c, C(O)OR.sub.c, CN, C(O)NR.sub.cR.sub.c, haloalkyl, haloalkoxy or OC.sub.1-6alkyl, being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13, (being R.sub.c, represented by R.sub.11, R.sub.12, R.sub.13; being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13; being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13), being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13) wherein R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are as defined in the description, and wherein when different radicals R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are present simultaneously in Formula I they may be identical or different.
(88) Most preferably in connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl, substituted is understood in the context of this invention that any alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl which, if substituted, is substituted with one or more of halogen (F, Cl, Br, I), OR.sub.c, CN, SR.sub.c, S(O)R.sub.c, S(O).sub.2R.sub.c, haloalkyl, haloalkoxy or OC.sub.1-6alkyl, being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13, (being R.sub.c, represented by R.sub.11, R.sub.12, R.sub.13; being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13; being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13, being R.sub.c represented by R.sub.11, R.sub.12, R.sub.13), wherein R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are as defined in the description, and wherein when different radicals R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are present simultaneously in Formula I, they may be identical or different.
(89) More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF.sub.3, or at different places of the same molecule, as in the case of e.g. CH(OH)CHCHCHCl.sub.2.
(90) In the context of this invention haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. CH.sub.2Cl, CH.sub.2F, CHCl.sub.2, CHF.sub.2, CCl.sub.3, CF.sub.3 and CH.sub.2CHCl.sub.2. Preferably haloalkyl is understood in the context of this invention as halogen-substituted C.sub.1-4-alkyl representing halogen substituted C1-, C2-, C3- or C4-alkyl. The halogen-substituted alkyl radicals are thus preferably methyl, ethyl, propyl, and butyl. Preferred examples include CH.sub.2Cl, CH.sub.2F, CHCl.sub.2, CHF.sub.2, and CF.sub.3.
(91) In the context of this invention haloalkoxy is understood as meaning an O-alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. OCH.sub.2Cl, OCH.sub.2F, OCHCl.sub.2, OCHF.sub.2, OCCl.sub.3, OCF.sub.3 and OCH.sub.2CHCl.sub.2. Preferably haloalkyl is understood in the context of this invention as halogen-substituted OC.sub.1-4-alkyl representing halogen substituted C1-, C2-, C3- or C4-alkoxy. The halogen-substituted alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include OCH.sub.2Cl, OCH.sub.2F, OCHCl.sub.2, OCHF.sub.2, and OCF.sub.3.
(92) In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Furthermore, C.sub.3-4-cycloalkyl represents C3- or C4-cycloalkyl, C.sub.3-5-cycloalkyl represents C3-, C4- or C5-cycloalkyl, C.sub.3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C.sub.3-7-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C.sub.3-8-cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C.sub.4-5-cycloalkyl represents C4- or C5-cycloalkyl, C.sub.4-6-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C.sub.4-7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C.sub.5-6-cycloalkyl represents C5- or C6-cycloalkyl and C.sub.5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantly. Preferably in the context of this invention cycloalkyl is C.sub.3-8cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C.sub.3-7cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C.sub.3-6cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.
(93) Aryl is understood as meaning 5 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, preferably is phenyl.
(94) A heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 5 to 18 membered mono or poly heterocyclic ring systems, with at least one saturated or unsaturated ring which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. A heterocyclic group can also be substituted once or several times.
(95) Examples include non-aromatic heterocyclyls such as tetrahydropyran, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazole, benzothiazole, indole, benzotriazole, carbazole and quinazoline.
(96) Subgroups inside the heterocyclyls as understood herein include heteroaryls and non-aromatic heterocyclyls. the heteroaryl (being equivalent to heteroaromatic radicals or aromatic heterocyclyls) is an aromatic 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one aromatic 5 to 18 membered ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is an aromatic 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two rings of which at least one aromatic ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole, indole, benzotriazole, carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole, thiophene and benzimidazole; the non-aromatic heterocyclyl is a 5 to 18 membered heterocyclic ring system of one or more rings of which at least one ringwith this (or these) ring(s) then not being aromaticcontains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two rings of which one or both ringswith this one or two rings then not being aromaticcontain/s one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepam, pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine, benzodioxane, oxetane, especially is benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine, oxetane and pyrrolidine.
(97) Preferably in the context of this invention heterocyclyl is defined as a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring.
(98) Preferred examples of heterocyclyls include oxetane, oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyridine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane, oxetane and pyrrolidine.
(99) In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2-one.
(100) In connection with aromatic heterocyclyls (heteroaryls), non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring system falls within two or more of the above cycle definitions simultaneously, then the ring system is defined first as an aromatic heterocyclyl (heteroaryl) if at least one aromatic ring contains a heteroatom. If no aromatic ring contains a heteroatom, then the ring system is defined as a non-aromatic heterocyclyl if at least one non-aromatic ring contains a heteroatom. If no non-aromatic ring contains a heteroatom, then the ring system is defined as an aryl if it contains at least one aryl cycle. If no aryl is present, then the ring system is defined as a cycloalkyl if at least one non-aromatic cyclic hydrocarbon is present.
(101) In the context of this invention alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through a C.sub.1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (CH.sub.2) groups. Most preferably alkylaryl is benzyl (i.e. CH.sub.2-phenyl).
(102) In the context of this invention alkylheterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through a C.sub.1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylheterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (CH.sub.2) groups. Most preferably alkylheterocyclyl is CH.sub.2-pyridine.
(103) In the context of this invention alkylcycloalkyl is understood as meaning an cycloalkyl group (see above) being connected to another atom through a C.sub.1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylcycloalkyl is understood as meaning an cycloalkyl group (see above) being connected to another atom through 1 to 4 (CH.sub.2) groups. Most preferably alkylcycloalkyl is CH.sub.2-cyclopropyl.
(104) Preferably, the aryl is a monocyclic aryl. More preferably the aryl is a 5, 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 5 or 6 membered monocyclic aryl.
(105) Preferably, the heteroaryl is a monocyclic heteroaryl. More preferably the heteroaryl is a 5, 6 or 7 membered monocyclic heteroaryl. Even more preferably the heteroaryl is a 5 or 6 membered monocyclic heteroaryl.
(106) Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl.
(107) Preferably, the cycloalkyl is a monocyclic cycloalkyl. More preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3, 4, 5 or 6 membered monocyclic cycloalkyl.
(108) In connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understoodunless defined otherwiseas meaning substitution of the ring-system of the aryl or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocyclyl or alkyl-heterocyclyl with one or more of halogen (F, Cl, Br, I), R.sub.c, OR.sub.c, CN, NO.sub.2, NR.sub.cR.sub.c, C(O)OR.sub.c, NR.sub.cC(O)R.sub.c, C(O)NR.sub.cR.sub.c, NR.sub.cS(O).sub.2R.sub.c, O, OCH.sub.2CH.sub.2OH, NR.sub.cC(O)NR.sub.cR.sub.c, S(O).sub.2NR.sub.cR.sub.c, NR.sub.cS(O).sub.2NR.sub.cR.sub.c, haloalkyl, haloalkoxy, SR.sub.c, S(O)R.sub.c, S(O).sub.2R.sub.c or C(CH.sub.3)OR.sub.c; NR.sub.cR.sub.c, with R.sub.c, R.sub.c, R.sub.c and R.sub.c independently being either H or a saturated or unsaturated, linear or branched, substituted or unsubstituted C.sub.1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted C.sub.1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted OC.sub.1-6-alkyl (alkoxy); a saturated or unsaturated, linear or branched, substituted or unsubstituted SC.sub.1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted C(O)C.sub.1-6-alkyl-group; a saturated or unsaturated, linear or branched, substituted or unsubstituted C(O)OC.sub.1-6-alkyl-group; a substituted or unsubstituted aryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl or alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or alkyl-heterocyclyl, being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14, (being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14), wherein R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are as defined in the description, and wherein when different radicals R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are present simultaneously in Formula I they may be identical or different.
(109) Most preferably in connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understood in the context of this invention that any aryl, cycloalkyl and heterocyclyl which is substituted is substituted (also in an alyklaryl, alkylcycloalkyl or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I), R.sub.c, OR.sub.c, CN, NO.sub.2, NR.sub.cR.sub.c, NR.sub.cC(O)R.sub.c, NR.sub.cS(O).sub.2R.sub.c, O, haloalkyl, haloalkoxy, or C(CH.sub.3)OR.sub.c; OC.sub.1-4alkyl being unsubstituted or substituted with one or more of OR.sub.c or halogen (F, Cl, I, Br), CN, or C.sub.1-4alkyl being unsubstituted or substituted with one or more of OR.sub.c or halogen (F, Cl, I, Br), being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14, (being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14; being R.sub.c one of R.sub.11, R.sub.12 or R.sub.14), wherein R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are as defined in the description, and wherein when different radicals R.sub.1 to R.sub.14 and R.sub.x, R.sub.x and R.sub.n are present simultaneously in Formula I they may be identical or different.
(110) Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocycyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understoodunless defined otherwiseas meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with
(111) ##STR00045##
(leading to a spiro structure) or O.
(112) Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understoodunless defined otherwiseas meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic alkyl-heterocyclyl is spirosubstituted or substituted with O.
(113) Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understoodunless defined otherwiseas meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with O.
(114) A ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with joined meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.
(115) The term leaving group means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl, Br, and I, and sulfonate esters, such as tosylate (TsO) or mesylate.
(116) The term salt is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions.
(117) The term physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxicespecially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
(118) These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the inventionusually a (deprotonated) acidas an anion with at least one, preferably inorganic, cation which is physiologically toleratedespecially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH.sub.4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
(119) Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically toleratedespecially if used on humans and/or mammals. By this is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically toleratedespecially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
(120) The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.
(121) Any compound that is a solvate of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term solvate according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.
(122) Any compound that is a prodrug of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. The term prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. Textbook of Drug design and Discovery Taylor & Francis (April 2002).
(123) Any compound that is an N-oxide of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention.
(124) Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by .sup.13C- or .sup.14C-enriched carbon or of a nitrogen by .sup.15N-enriched nitrogen are within the scope of this invention.
(125) The compounds of formula (I) as well as their salts or solvates of the compounds are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts. This applies also to its solvates or prodrugs.
(126) In a more particular embodiment the compound according to the invention of general Formula (I)
(127) ##STR00046##
is a compound wherein
R.sub.1 is
(128) ##STR00047##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1, if substituted, may also be substituted
(129) ##STR00048##
with or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(130) ##STR00049##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
and wherein
(131) ##STR00050##
is selected from
(132) ##STR00051##
wherein R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.13, halogen, CN, haloalkyl, haloalkoxy, SR.sub.13, S(O)R.sub.13, and S(O).sub.2R.sub.13; wherein R.sub.13, and R.sub.13, are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl;
the aryl, heterocyclyl or cycloalkyl other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.14, OR.sub.14, NO.sub.2, NR.sub.14R.sub.14, NR.sub.14C(O)R.sub.14, NR.sub.14S(O).sub.2R.sub.14, S(O).sub.2NR.sub.14R.sub.14, NR.sub.14C(O)NR.sub.14R.sub.14, SR.sub.14, S(O)R.sub.14, S(O).sub.2R.sub.14, CN, haloalkyl, haloalkoxy, C(O)OR.sub.14, C(O)NR.sub.14R.sub.14, OCH.sub.2CH.sub.2OH, NR.sub.14S(O).sub.2NR.sub.14R.sub.14 and C(CH.sub.3).sub.2OR.sub.14;
additionally, wherein cycloalkyl or non-aromatic heterocyclyl, other than those defined in R.sub.1 or R.sub.2, if substituted, may also be substituted with
(133) ##STR00052##
or O; wherein R.sub.14, R.sub.14 and R.sub.14 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and wherein R.sub.14 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
(134) These preferred compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(135) In one further embodiment W is N or CH.
(136) In one further embodiment W is N.
(137) In one further embodiment W is CH.
(138) In one further embodiment
(139) R.sub.1 is or
(140) ##STR00053##
and
R.sub.1 is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl. wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1, if substituted, may also be substituted with
(141) ##STR00054##
or O; wherein R.sub.11, R.sub.11, and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc.
(142) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(143) m is 1, 2 or 3;
(144) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(145) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(146) n is 0, 1 or 2;
(147) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(148) In a further embodiment the compound according to the invention of general f Formula (I) is a compound wherein
(149) p is 0, 1 or 2;
(150) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(151) In a further embodiment the compound according to the invention of general f Formula (I) is a compound wherein
(152) q is 0 or 1;
(153) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(154) In a further embodiment the compound according to the invention of general f Formula (I) is a compound wherein
(155) W is nitrogen or carbon;
(156) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(157) In a further embodiment the compound according to the invention of general f Formula (I) is a compound wherein
(158) W is nitrogen;
(159) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(160) In a further embodiment the compound according to the invention of general f Formula (I) is a compound wherein
(161) W is carbon;
(162) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(163) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(164) X is a bond, C(R.sub.xR.sub.x), CO or O;
(165) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(166) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(167) X is a bond;
(168) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(169) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(170) X is C(R.sub.xR.sub.x);
(171) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(172) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(173) X is CO;
(174) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(175) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(176) X is O;
(177) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(178) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(179) R.sub.1 is
(180) ##STR00055##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(181) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(182) R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(183) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(184) R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
(185) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(186) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(187) R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(188) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(189) R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
(190) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(191) In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein
(192) R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
(193) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(194) In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein
(195) R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(196) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(197) In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein
(198) R.sub.3 and R.sub.3 are independently selected from hydrogen and substituted or unsubstituted C.sub.1-6 alkyl;
(199) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(200) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(201) R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(202) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(203) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(204) R.sub.4 and R.sub.4 are independently selected from hydrogen and substituted or unsubstituted C.sub.1-6 alkyl;
(205) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(206) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(207) R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
(208) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(209) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(210) R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(211) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(212) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(213) R.sub.4 and R.sub.4 are independently selected from hydrogen and substituted or unsubstituted C.sub.1-6 alkyl;
(214) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(215) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(216) R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
(217) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(218) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(219) R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8;
(220) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(221) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(222) R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl and substituted or unsubstituted C.sub.2-6 alkenyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(223) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(224) R.sub.5 and R.sub.5 are independently selected from hydrogen and substituted or unsubstituted C.sub.1-6 alkyl;
(225) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(226) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(227) R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(228) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(229) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(230) R.sub.6 and R.sub.6 are independently selected from hydrogen and OR.sub.9; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(231) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(232) R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(233) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(234) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(235) R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(236) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(237) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(238) R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(239) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(240) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(241) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(242) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.11, R.sub.11, and R.sub.11 are independently selected from hydrogen and unsubstituted C.sub.1-6 alkyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(243) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(244) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(245) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(246) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(247) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.13 and R.sub.13 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(248) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.14, R.sub.14 and R.sub.14 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and wherein R.sub.14 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(249) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.14, R.sub.14 and R.sub.14 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(250) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.14 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(251) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(252) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(253) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(254) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(255) R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
(256) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(257) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(258) R.sub.n is unsubstituted C.sub.1-6 alkyl;
(259) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(260) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(261) ##STR00056##
is selected from
(262) ##STR00057##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(263) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(264) ##STR00058##
is
(265) ##STR00059##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(266) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(267) ##STR00060##
is
(268) ##STR00061##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(269) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(270) ##STR00062##
is
(271) ##STR00063##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(272) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(273) ##STR00064##
is
(274) ##STR00065##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(275) In another preferred embodiment of the compound according to the invention of general Formula (I) is a compound wherein
(276) ##STR00066##
is
(277) ##STR00067##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(278) In another preferred embodiment of the compound according to the invention of general Formula (I), is a compound wherein
(279) R.sub.1 is
(280) ##STR00068##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is ethyl, methyl, or isopropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene, more preferably the C.sub.2-6-alkenyl is vinyl;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, more preferably the heterocyclyl is pyridine;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably the cycloalkyl is cyclopropyl; and/or
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl,
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl, ethyl, isopropyl, isobutyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene, more preferably the C.sub.2-6-alkenyl is 2-methylprop-1-enyl;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphthyl and anthracene; preferably is naphthyl or phenyl; more preferably is phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline; more preferably the heterocyclyl is pyridine;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably the cycloalkyl is cyclopentyl;
and/or
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably the cycloalkyl is cyclopentyl;
and/or
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
and R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
and R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.13 and R.sub.13 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.14, R.sub.14 and R.sub.14 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;
and R.sub.14 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
the aryl is selected from phenyl, naphthyl and anthracene; preferably is naphthyl or phenyl;
and/or
the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or
R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
and/or
R.sub.n is selected from unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl;
wherein
the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, preferably the C.sub.1-6 alkyl is methyl;
and/or
the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
and/or
the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(281) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.1 as defined in any of the embodiments of the present invention,
(282) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is ethyl, methyl, or isopropyl;
(283) and/or
(284) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene, more preferably, the C.sub.2-6-alkenyl is vinyl;
(285) and/or
(286) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(287) and/or
(288) the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; more preferably is phenyl;
(289) and/or
(290) the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, more preferably the heterocycle is pyridine;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably the cycloalkyl is cyclopropyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(291) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.2 as defined in any of the embodiments of the present invention,
(292) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl, ethyl, isopropyl, isobutyl;
(293) and/or
(294) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene, more preferably, the C.sub.2-6-alkenyl is 2-methylprop-1-enyl;
(295) and/or
(296) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(297) and/or
(298) the aryl is selected from phenyl, naphthyl and anthracene; preferably is naphthyl or phenyl; more preferably is phenyl;
(299) and/or
(300) the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline; more preferably the heterocyclyl is pyridine;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(301) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.3 as defined in any of the embodiments of the present invention,
(302) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more preferably the C.sub.1-6 alkyl is methyl;
(303) and/or
(304) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(305) and/or
(306) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(307) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(308) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.4 and R.sub.4 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
(309) and/or
(310) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(311) and/or
(312) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(313) and/or
(314) the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably the cycloalkyl is cyclopentyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(315) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.4 and R.sub.4 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
(316) and/or
(317) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(318) and/or
(319) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(320) and/or
(321) the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably the cycloalkyl is cyclopentyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(322) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.5 and R.sub.5 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; more preferably the C.sub.1-6 alkyl is methyl;
(323) and/or
(324) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(325) and/or
(326) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(327) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(328) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.6 and R.sub.6 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(329) and/or
(330) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(331) and/or
(332) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(333) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(334) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.7 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(335) and/or
(336) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(337) and/or
(338) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(339) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(340) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.8 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(341) and/or
(342) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(343) and/or
(344) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(345) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(346) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.9 and R.sub.9 as defined in any of the embodiments of the present invention, the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(347) and/or
(348) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(349) and/or
(350) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(351) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(352) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.11, R.sub.11 and R.sub.11 as defined in any of the embodiments of the present invention,
(353) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, more preferably, the C.sub.1-6 alkyl is methyl;
(354) and/or
(355) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(356) and/or
(357) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(358) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(359) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.11 as defined in any of the embodiments of the present invention,
(360) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(361) and/or
(362) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(363) and/or
(364) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(365) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(366) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.12, R.sub.12 and R.sub.12 as defined in any of the embodiments of the present invention,
(367) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(368) and/or
(369) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(370) and/or
(371) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(372) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(373) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.12 as defined in any of the embodiments of the present invention,
(374) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(375) and/or
(376) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(377) and/or
(378) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(379) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(380) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.13 and R.sub.13 as defined in any of the embodiments of the present invention,
(381) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(382) and/or
(383) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(384) and/or
(385) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(386) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(387) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.14, R.sub.14 and R.sub.14 as defined in any of the embodiments of the present invention,
(388) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(389) and/or
(390) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(391) and/or
(392) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(393) and/or
(394) the aryl is selected from phenyl, naphthyl and anthracene; preferably is naphthyl or phenyl;
(395) and/or
(396) the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline;
and/or
the cycloalkyl is C.sub.3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C.sub.3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C.sub.3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(397) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.14 as defined in any of the embodiments of the present invention,
(398) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(399) and/or
(400) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(401) and/or
(402) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(403) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(404) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.n as defined in any of the embodiments of the present invention,
(405) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl, preferably the C.sub.1-6 alkyl is methyl;
(406) and/or
(407) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(408) and/or
(409) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(410) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(411) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.x as defined in any of the embodiments of the present invention,
(412) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(413) and/or
(414) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(415) and/or
(416) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(417) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(418) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R.sub.x, as defined in any of the embodiments of the present invention,
(419) the C.sub.1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl;
(420) and/or
(421) the C.sub.2-6-alkenyl is preferably selected from ethylene, propylene, butylene, pentylene and hexylene;
(422) and/or
(423) the C.sub.2-6-alkynyl is preferably selected from ethyne, propyne, butyne, pentyne and hexyne;
(424) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(425) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(426) n is 0, 1 or 2; preferably n is 0;
(427) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(428) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(429) m is 1, 2 or 3; preferably m is 1 or 2;
(430) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(431) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(432) p is 0, 1 or 2; preferably p is 0 or 1;
(433) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(434) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(435) q is 0 or 1;
(436) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(437) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(438) W is nitrogen or carbon;
(439) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(440) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(441) X is a bond, C(R.sub.xR.sub.x), CO or O; preferably, X is a bond or O;
(442) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(443) In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(444) Y is S or O; preferably, Y is O;
(445) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(446) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein X is a bond, C(R.sub.xR.sub.x), CO or O; preferably X is a bond or O; and/or m is 1, 2 or 3; preferably m is 1 or 2; and/or n is 0, 1 or 2; preferably n is 0; and/or p is 0, 1 or 2; preferably p is 0 or 1; and/or q is 0 or 1; preferably q is 1;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(447) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(448) ##STR00069##
is
(449) ##STR00070## W is nitrogen or carbon; preferably W is nitrogen;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(450) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(451) ##STR00071##
is
(452) ##STR00072## W is nitrogen or carbon; preferably W is nitrogen, and R.sub.n is unsubstituted C.sub.1-6 alkyl, preferably unsubstituted methyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(453) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(454) ##STR00073##
is
(455) ##STR00074## W is nitrogen or carbon; preferably W is nitrogen, and R.sub.n is unsubstituted C.sub.1-6 alkyl, preferably unsubstituted methyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(456) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(457) ##STR00075##
is
(458) ##STR00076## W is nitrogen or carbon; preferably W is nitrogen;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(459) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein
(460) ##STR00077##
is
(461) ##STR00078## W is nitrogen or carbon; preferably W is nitrogen;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(462) In another preferred embodiment of the invention according to general Formula (I), the compound is a compound of Formula (I.sup.3)
(463) ##STR00079##
wherein
R.sub.1 is
(464) ##STR00080##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11, and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1, if substituted, may also be substituted with
(465) ##STR00081##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(466) ##STR00082##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.3 and R.sub.3 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(467) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound of Formula (I.sup.4),
(468) ##STR00083##
wherein
R.sub.1 is
(469) ##STR00084##
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11, and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1, if substituted, may also be substituted with
(470) ##STR00085##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(471) ##STR00086##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(472) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound of Formula (I.sup.4a),
(473) ##STR00087##
wherein
R.sub.1 is or
(474) ##STR00088##
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0 or 1;
W is nitrogen or carbon;
X is a bond, C(R.sub.xR.sub.x), CO or O; wherein R.sub.x is selected from halogen, OR.sub.7, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.x is selected from hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; R.sub.7 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
Y is S or O;
R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1 if substituted, may also be substituted with
(475) ##STR00089##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(476) ##STR00090##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl,
alternatively, R.sub.4 and R.sub.4, may form together with the carbon atom to which they are attached a substituted or unsubstituted cycloalkyl;
R.sub.5, R.sub.5, R.sub.5 and R.sub.5 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, CHOR.sub.8 and C(O)OR.sub.8; wherein R.sub.8 is selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
R.sub.6 and R.sub.6 are independently selected from hydrogen, OR.sub.9, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl; wherein R.sub.9 and R.sub.9 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(477) In a further preferred embodiment of the invention according to general Formula (I) the compound is a compound of Formula (I.sup.4b),
(478) ##STR00091##
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(479) In a preferred embodiment
(480) R.sub.1 is a substituted or unsubstituted group selected from methyl, ethyl, isopropyl, vinyl, cyclopropyl, phenyl, pyridine, benzyl, CH(OH)-pyridine, C(O)-pyridine and C(O)-phenyl.
(481) In a preferred embodiment
(482) R.sub.1 is a substituted or unsubstituted group selected from methyl, ethyl, isopropyl, vinyl, cyclopropyl, phenyl and pyridine.
(483) In a preferred embodiment
(484) R.sub.2 is a substituted or unsubstituted group selected from methyl, ethyl, isopropyl, isobutyl, 2-methylprop-1-enyl, CH.sub.2C(CH.sub.3).sub.2OH, CH.sub.2C(CH.sub.3).sub.2F, phenyl and pyridine, more preferably an unsubstituted group selected from methyl, ethyl, isopropyl, isobutyl, 2-methylprop-1-enyl, phenyl and pyridine.
(485) In another preferred embodiment
(486) R.sub.2 is a substituted or unsubstituted group selected from methyl, ethyl, isopropyl, isobutyl, 2-methylprop-1-enyl, CH.sub.2C(CH.sub.3).sub.2OH, CH.sub.2C(CH.sub.3).sub.2F, phenyl, pyrazole 1-phenyl-1H-pyrazole-3-yl, 1-phenyl-1H-pyrazole-4-yl and pyridine, more preferably a substituted or unsubstituted group selected from methyl, ethyl, isopropyl, isobutyl, 2-methylprop-1-enyl, phenyl and pyridine, even more preferably a substituted or unsubstituted group selected from isopropyl, isobutyl, phenyl and pyridine
(487) In a preferred embodiment
(488) R.sub.2 is a substituted or unsubstituted group selected from
(489) ##STR00092##
preferably, R.sub.2 is an unsubstituted group selected from
(490) ##STR00093##
(491) In a preferred embodiment
(492) R.sub.3 is hydrogen or substituted or unsubstituted methyl.
(493) In a preferred embodiment
(494) R.sub.3 is hydrogen.
(495) In a preferred embodiment
(496) R.sub.3 is hydrogen or substituted or unsubstituted methyl, while R.sub.3 is hydrogen.
(497) In a preferred embodiment
(498) R.sub.3 is substituted or unsubstituted methyl, while R.sub.3 is hydrogen.
(499) In a preferred embodiment
(500) R.sub.3 and R.sub.3 are both hydrogen.
(501) In a preferred embodiment
(502) R.sub.4 is hydrogen or substituted or unsubstituted methyl, preferably R.sub.4 is hydrogen or unsubstituted methyl.
(503) In a preferred embodiment
(504) R.sub.4 is hydrogen or substituted or unsubstituted methyl, preferably R.sub.4, is hydrogen or unsubstituted methyl.
(505) In a preferred embodiment
(506) R.sub.4 and R.sub.4 are both hydrogen.
(507) In a preferred embodiment
(508) R.sub.4 and R.sub.4 are both substituted or unsubstituted methyl, preferably R.sub.4 and R.sub.4 are both unsubstituted methyl.
(509) In a preferred embodiment
(510) R.sub.4 is substituted or unsubstituted methyl, preferably unsubstituted methyl, while R.sub.4 is hydrogen
(511) In a preferred embodiment
(512) R.sub.4 is hydrogen, while R.sub.4 is substituted or unsubstituted methyl, preferably unsubstituted methyl.
(513) In a preferred embodiment
(514) R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl;
(515) or
(516) may form together with the carbon atom to which they are attached a substituted or unsubstituted C.sub.3-6 cycloalkyl; preferably substituted or unsubstituted cyclopentyl
(517) and/or
R.sub.4 and R.sub.4 are independently selected from hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl and substituted or unsubstituted C.sub.2-6 alkynyl.
(518) In a preferred embodiment
(519) R.sub.4 and R.sub.4 are both substituted or unsubstituted methyl, preferably R.sub.4 and R.sub.4 are both unsubstituted methyl.
(520) or
(521) R.sub.4 and R.sub.4 form together with the carbon atom to which they are attached a substituted or unsubstituted cyclopentyl, preferably an unsubstituted cyclopentyl.
(522) In a preferred embodiment
(523) R.sub.4 and R.sub.4 are both substituted or unsubstituted methyl, preferably R.sub.4 and R.sub.4 are both unsubstituted methyl.
(524) In a preferred embodiment
(525) R.sub.4 and R.sub.4 form together with the carbon atom to which they are attached a substituted or unsubstituted cyclopentyl, preferably an unsubstituted cyclopentyl.
(526) In a preferred embodiment
(527) R.sub.4 is hydrogen or substituted or unsubstituted methyl, preferably R.sub.4 is hydrogen or unsubstituted methyl.
(528) In a preferred embodiment
(529) R.sub.4 is hydrogen or substituted or unsubstituted methyl, preferably R.sub.4 is hydrogen or unsubstituted methyl.
(530) In a preferred embodiment
(531) R.sub.4 and R.sub.4 are both hydrogen.
(532) In a preferred embodiment
(533) R.sub.4 and R.sub.4 are both substituted or unsubstituted methyl, preferably R.sub.4 and R.sub.4 are both unsubstituted methyl
(534) In a preferred embodiment
(535) R.sub.4 and R.sub.4 form together with the carbon atom to which they are attached a substituted or unsubstituted cyclopentyl, preferably unsubstituted cyclopentyl
(536) In a preferred embodiment
(537) R.sub.4 is substituted or unsubstituted methyl, preferably unsubstituted methyl, while R.sub.4, is hydrogen
(538) In a preferred embodiment
(539) R.sub.4 is hydrogen, while R.sub.4 is substituted or unsubstituted methyl, preferably unsubstituted methyl.
(540) In a preferred embodiment
(541) R.sub.5 is hydrogen or substituted or unsubstituted methyl, preferably R.sub.5 is hydrogen or unsubstituted methyl.
(542) In a preferred embodiment
(543) R.sub.5 is hydrogen.
(544) In a preferred embodiment
(545) R.sub.5 is hydrogen or substituted or unsubstituted methyl, while R.sub.5 is hydrogen, preferably R.sub.5 is hydrogen or unsubstituted methyl, while R.sub.5 is hydrogen.
(546) In a preferred embodiment
(547) R.sub.5 is substituted or unsubstituted methyl, while R.sub.5 is hydrogen, preferably R.sub.5 is unsubstituted methyl, while R.sub.5 is hydrogen.
(548) In a preferred embodiment
(549) R.sub.5 and R.sub.5 are both hydrogen.
(550) In a preferred embodiment
(551) R.sub.6 is hydrogen or OH.
(552) In a preferred embodiment
(553) R.sub.6 is hydrogen.
(554) In a preferred embodiment
(555) R.sub.6 is hydrogen or OH, while R.sub.6 is hydrogen.
(556) In a preferred embodiment
(557) R.sub.6 is OH, while R.sub.6 is hydrogen.
(558) In a preferred embodiment
(559) R.sub.6 and R.sub.6 are both hydrogen.
(560) In a preferred embodiment
(561) R.sub.9 is hydrogen.
(562) In a preferred embodiment
(563) R.sub.11 is hydrogen or substituted or unsubstituted methyl, more preferably hydrogen or unsubstituted methyl.
(564) In a preferred embodiment
(565) R.sub.12 is hydrogen.
(566) In a preferred embodiment
(567) R.sub.n is substituted or unsubstituted methyl, preferably unsubstituted methyl.
(568) In a preferred embodiment
(569) X is a bond or O.
(570) In a preferred embodiment
(571) Y is O.
(572) In a preferred embodiment
(573) W is nitrogen or carbon.
(574) In another preferred embodiment
(575) n is 0.
(576) In another preferred embodiment
(577) m is 1, 2 or 3;
(578) In another preferred embodiment
(579) m is 1 or 2;
(580) In another preferred embodiment
(581) p is 0 or 1.
(582) In another preferred embodiment
(583) q is 0 or 1.
(584) In an particular embodiment
(585) the halogen is fluorine or chlorine.
(586) In an particular embodiment
(587) the haloalkyl is CF.sub.3.
(588) In a preferred further embodiment, the compounds of the general Formula (I) are selected from
(589) TABLE-US-00001 EX Chemical name 1 (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)(pyridin-2-yl)methanone 2 (S)-(4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 3 (R)-(4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 4 (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9- yl)(phenyl)methanone 5 (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9- yl)(pyridin-2-yl)methanone 6 (9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9- yl)(6-(trifluoromethyl)pyridin-2-yl)methanone 7 (9-(4-isobutylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9- yl)(phenyl)methanone 8 (4-(4-benzylpiperazin-1-yl)tetrahydro-2H-pyran-4- yl)(pyridin-2-yl)methanone 9 (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(phenyl)methanone 10 (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-3-yl)methanone 11 (4-(4-isobutylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(phenyl)methanone 12 (4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(phenyl)methanone 13 (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(phenyl)methanone 14 (4-(4-isobutylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 15 (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)(6-(trifluoromethyl)pyridin-2-yl)methanone 16 (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(6- (trifluoromethyl)pyridin-2-yl)methanone 17 (4-(4-benzylpiperazin-1-yl)-2,2,6,6-tetramethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 18 (4-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 19 (4-(3-(benzyl(methyl)amino)azetidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 20 (3-(4-benzylpiperazin-1-yl)tetrahydrofuran-3-yl)(pyridin-2- yl)methanone 21 (4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin- 2-yl)methanone 22 (4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)(pyridin-2-yl)methanone 23 (4-(3-((2-isopropoxyethyl)(methyl)amino)azetidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 24 (4-(4-benzyl-1,4-diazepan-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 25 4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4- yl)(pyridin-2-yl)methanone 26 2-methyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4- yl)(pyridin-2-yl)methanone 27 (2S,4R)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 28 (2R,4S)-4-(4-benzylpiperazin-1-yl)-2-methyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 29 1-benzyl-4-(9-ethyl-6-oxaspiro[4.5]decan-9-yl)piperazine 30 1-benzyl-4-(4-phenyltetrahydro-2H-pyran-4-yl)piperazine 31 1-benzyl-4-(4-ethyltetrahydro-2H-pyran-4yl)piperazine 32 1-benzyl-4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine 33 1-isobutyl-4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine 34 1-benzyl-4-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)piperazine 35 1-benzyl-4-(2,2-dimethyl-4-phenyltetrahydro-2H-pyran-4- yl)piperazine 36 1-benzyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4- yl)piperazine 37 1-(2-isopropoxyethyl)-4-(2,2,4-trimethyltetrahydro-2H-pyran- 4-yl)piperazine 38 1-benzyl-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4- yl)piperazine 39 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- isopropoxyethyl)piperazine 40 1-benzyl-4-(4-benzyl-2,2-dimethyltetrahydro-2H-pyran-4- yl)piperazine 41 1-(2,2-dimethyl-4-propyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 42 1-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 43 1-benzyl-4-(4-isopropyl-2,2-dimethyltetrahydro-2H-pyran-4- yl)piperazine 44 1-(4-cyclopropyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 45 1-(2,2-dimethyl-4-vinyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 46 1-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 47 1-(4-ethyl-2-methyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 48 2-(2,2-dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H- pyran-4-yl)ethanol 49 1-(4-(2-Methoxyethyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)- 4-phenethylpiperazine 50 (2,2-dimethyl-4-(4-(pyridin-2-ylmethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 51 (9-(4-isobutylpiperazin-1-yl)-6-oxaspiro[4.5]decan-9- yl)(pyridin-2-yl)methanone 52 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 53 1-phenethyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4- yl)piperazine 54 (2,2-dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 55 (4-(4-(2-(3-fluoropyridin-2-yl)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 56 (4-(4-(2-(3-chloropyridin-2-yl)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 57 (4-(4-(2-(3-chloropyridin-4-yl)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 58 (2,2-dimethyl-4-(4-(pyridin-3-ylmethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 59 (2,2-dimethyl-4-(4-(pyridin-4-ylmethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 60 (4-(4-(4-fluorobenzyl)piperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 61 (4-(4-(3-fluorobenzyl)piperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 62 (2,2-dimethyl-4-(4-(1-phenylethyl)piperazin-1-yl)tetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 63 (4-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 64 (4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 65 (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 66 (4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 67 (4-(4-(2-ethoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 68 (4-(4-(2-methoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 69 (2,2-dimethyl-4-(4-(2-(2,2,2-trifluoroethoxy)ethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 70 (4-(4-(2-(2-hydroxy-2-methylpropoxy)ethyl)piperazin-1-yl)- 2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 71 (4-(4-(3-isopropoxypropyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 72 (4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 73 (4-(5-(2-isopropoxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2- yl)methanone 74 (3-(4-(2-isopropoxyethyl)piperazin-1-yl)tetrahydrofuran-3- yl)(pyridin-2-yl)methanone 75 2-(4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)pyridine 76 (4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 77 (4-(1-(2-isopropoxyethyl)piperidin-4-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 78 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- isopentylpiperazine 79 1-isopentyl-4-(2,2,4-trimethyltetrahydro-2H-pyran-4- yl)piperazine 80 (2,2-dimethyl-4-(4-(2-(pyridin-3-yl)ethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 81 (2,2-dimethyl-4-(4-(2-(pyridin-4-yl)ethyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 82 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- (pyridin-4-yl)ethyl)piperazine 83 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- (pyridin-3-yl)ethyl)piperazine 84 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- (3-fluoropyridin-4-yl)ethyl)piperazine 85 (4-(4-(2-(3-fluoropyridin-4-yl)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 86 (4-(4-isopentyl-1,4-diazepan-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 87 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- (pyridin-2-yl)ethyl)piperazine 88 (4-(4-(2-isopropoxyethyl)-1,4-diazepan-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 89 1-(2-fluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro- 2H-pyran-4-yl)piperazine 90 (4-(4-(3-hydroxy-3-methylbutyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 91 1-(3-fluorophenethyl)-4-(4-isopropyl-2,2-dimethyltetrahydro- 2H-pyran-4-yl)piperazine 92 1-(2,5-difluorophenethyl)-4-(4-isopropyl-2,2- dimethyltetrahydro-2H-pyran-4-yl)piperazine 93 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(3- fluorophenethyl)piperazine 94 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(2- fluorophenethyl)piperazine 95 (2R,4S)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2- methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 96 (2S,4R)-4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2- methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 97 (2R,4S)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 98 (2S,4R)-4-(4-isopentylpiperazin-1-yl)-2-methyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 99 1-(2,5-difluorophenethyl)-4-(4-ethyl-2,2-dimethyltetrahydro- 2H-pyran-4-yl)piperazine 100 1-(2,3-difluorophenethyl)-4-(4-ethyl-2,2-dimethyltetrahydro- 2H-pyran-4-yl)piperazine 101 1-(2,3-difluorophenethyl)-4-(4-isopropyl-2,2- dimethyltetrahydro-2H-pyran-4-yl)piperazine 102 (4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 103 (4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 104 (4-(1-(3-ethoxypropyl)piperidin-4-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 105 (4-(1-(2-ethoxyethyl)piperidin-4-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 106 (4-(1-(2-isobutoxyethyl)piperidin-4-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 107 (4-(1-(3-isopropoxypropyl)piperidin-4-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 108 (4-(1-(3-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 109 (4-(1-(4-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 110 (4-(1-(2-fluorobenzyl)piperidin-4-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 111 (4-(4-(2-fluorophenethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 112 (S)-1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 113 (R) 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4- phenethylpiperazine 114 (S)-(4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone, 115 (R)-(4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)(pyridin-2-yl)methanone 116 (4-(4-(2-(2-fluoro-2-methylpropoxy)ethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 117 (4-(4-(3-fluoro-3-methylbutyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 118 (2,2-Dimethyl-4-(4-(3-methylbut-3-enyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 119 1-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-3- ylmethyl)piperazine 120 1-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-2- ylmethyl)piperazine 121 3-((4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazin-1- yl)methyl)benzonitrile 122 1-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-3- ylmethyl)piperazine 123 1-(9-benzyl-6-oxaspiro[4.5]decan-9-yl)-4-isobutylpiperazine 124 2-(4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4- yl)pyridine 125 2-(4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)pyridine 126 2-(4-(1-isobutylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H- pyran-4-yl)pyridine 127 (2,2-dimethyl-4-(4-(3,3,3-trifluoropropyl)piperazin-1- yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 128 (4-(4-(2-cyclopropylethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 129 (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)(pyridin-2-yl)methanol 130 (4-(1-benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-yl)(pyridin- 2-yl)methanol 131 (4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)(pyridin-2-yl)methanol 132 (S)-(4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 133 (R)-(4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)(pyridin-2-yl)methanone 134 (S)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 135 (R)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 136 (S)-(4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 137 (R)-(4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 138 (4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 139 (R)-(4-(4-(2-isopropoxyethyl)piperazin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 140 ((S)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 141 ((R)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone 142 (R) 4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone. 143 (S) 4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2- dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone.
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(590) In a preferred further embodiment, the compounds of the general Formula (I) are selected from
(591) TABLE-US-00002 Ex Structure Chemical name 144
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(592) In another preferred further embodiment, the compounds of the general Formula (I) are selected from
(593) TABLE-US-00003 Ex Structure Chemical name 144
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(594) In a preferred embodiment of the compound according to the invention of general Formula (I),
(595) R.sub.1 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein said cycloalkyl, aryl or heterocyclyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.1, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.1 if substituted, may also be substituted with
(596) ##STR00308##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11; wherein R.sub.11, R.sub.11 and R.sub.11 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.11 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(597) In another embodiment of the invention the compound of general Formula (I),
(598) R.sub.2 is selected from substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl, wherein said cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12; additionally, cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(599) ##STR00309##
or O; wherein the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12; wherein R.sub.12, R.sub.12 and R.sub.12 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl and unsubstituted C.sub.2-6 alkynyl; and wherein R.sub.12 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(600) In another embodiment of the invention the compound of general Formula (I),
(601) the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.13, halogen, CN, haloalkyl, haloalkoxy, SR.sub.13, S(O)R.sub.13, and S(O).sub.2R.sub.13;
(602) wherein R.sub.13 and R.sub.13 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, and unsubstituted C.sub.2-6 alkynyl;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(603) In another embodiment of the invention the compound of general Formula (I),
(604) the aryl, heterocyclyl or cycloalkyl other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.14, OR.sub.14, NO.sub.2, NR.sub.14R.sub.14, NR.sub.14C(O)R.sub.14, NR.sub.14S(O).sub.2R.sub.14, S(O).sub.2NR.sub.14R.sub.14, NR.sub.14C(O)NR.sub.14R.sub.14, SR.sub.14, S(O)R.sub.14, S(O).sub.2R.sub.14, ON, haloalkyl, haloalkoxy, C(O)OR.sub.14, C(O)NR.sub.14R.sub.14, OCH.sub.2CH.sub.2OH, NR.sub.14S(O).sub.2NR.sub.14R.sub.14 and C(CH.sub.3).sub.2OR.sub.14;
additionally, wherein cycloalkyl or non-aromatic heterocyclyl, other than those defined in R.sub.1 or R.sub.2, if substituted, may also be substituted with
(605) ##STR00310##
or O; wherein R.sub.14, R.sub.14 and R.sub.14 are independently selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and wherein R.sub.14 is selected from hydrogen, unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.2-6 alkenyl, unsubstituted C.sub.2-6 alkynyl and -Boc;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(606) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.1 of any of the embodiments of the present invention, the cycloalkyl, aryl or heterocyclyl in R.sub.1, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.11, OR.sub.11, NO.sub.2, NR.sub.11R.sub.11, NR.sub.11C(O)R.sub.11, NR.sub.11S(O).sub.2R.sub.11, S(O).sub.2NR.sub.11R.sub.11, NR.sub.11C(O)NR.sub.11R.sub.11, SR.sub.11, S(O)R.sub.11, S(O).sub.2R.sub.11, CN, haloalkyl, haloalkoxy, C(O)OR.sub.11, C(O)NR.sub.11R.sub.11, OCH.sub.2CH.sub.2OH, NR.sub.11S(O).sub.2NR.sub.11R.sub.11 and C(CH.sub.3).sub.2OR.sub.11;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(607) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.1 of any of the embodiments of the present invention, the cycloalkyl, aryl or heterocyclyl in R.sub.1 if substituted, is substituted with CF.sub.3
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(608) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.1 of any of the embodiments of the present invention,
(609) the cycloalkyl or non-aromatic heterocyclyl in R.sub.1 if substituted, may also be substituted with
(610) ##STR00311##
or O;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(611) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.1 of any of the embodiments of the present invention,
(612) the alkyl, alkenyl or alkynyl in R.sub.1 if substituted, is substituted with one or more substituent/s selected from OR.sub.11, halogen, CN, haloalkyl, haloalkoxy, SR.sub.11, S(O)R.sub.11, and S(O).sub.2R.sub.11;
(613) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(614) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.2 of any of the embodiments of the present invention, the cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.12, OR.sub.12, NO.sub.2, NR.sub.12R.sub.12, NR.sub.12C(O)R.sub.12, NR.sub.12S(O).sub.2R.sub.12, S(O).sub.2NR.sub.12R.sub.12, NR.sub.12C(O)NR.sub.12R.sub.12, SR.sub.12, S(O)R.sub.12, S(O).sub.2R.sub.12, CN, haloalkyl, haloalkoxy, C(O)OR.sub.12, C(O)NR.sub.12R.sub.12, OCH.sub.2CH.sub.2OH, NR.sub.12S(O).sub.2NR.sub.12R.sub.12 and C(CH.sub.3).sub.2OR.sub.12;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(615) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.2 of any of the embodiments of the present invention, the cycloalkyl, aryl or heterocyclyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from fluorine, chlorine, -methoxy, CN, CF.sub.3 and OCF.sub.3;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(616) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.2 of any of the embodiments of the present invention, the cycloalkyl or non-aromatic heterocyclyl in R.sub.2, if substituted, may also be substituted with
(617) ##STR00312##
or O;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(618) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.2 of any of the embodiments of the present invention,
(619) the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.12, halogen, CN, haloalkyl, haloalkoxy, SR.sub.12, S(O)R.sub.12, and S(O).sub.2R.sub.12;
(620) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(621) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to R.sub.2 of any of the embodiments of the present invention,
(622) the alkyl, alkenyl or alkynyl in R.sub.2, if substituted, is substituted with one or more substituent/s selected from OH, fluorine and CF.sub.3;
(623) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(624) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to alkyls other than those defined in R.sub.1 or R.sub.2 of any of the embodiments of the present invention,
(625) the alkyl, alkenyl or alkynyl, other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from OR.sub.13, halogen, CN, haloalkyl, haloalkoxy, SR.sub.13, S(O)R.sub.13, and S(O).sub.2R.sub.13;
(626) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(627) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to the cycloalkyl, aryl or heterocyclyl other than those defined in R.sub.1 or R.sub.2 of any of the embodiments of the present invention,
(628) the aryl, heterocyclyl or cycloalkyl other than those defined in R.sub.1 or R.sub.2, if substituted, is substituted with one or more substituent/s selected from halogen, R.sub.14, OR.sub.14, NO.sub.2, NR.sub.14R.sub.14, NR.sub.14C(O)R.sub.14, NR.sub.14S(O).sub.2R.sub.14, S(O).sub.2NR.sub.14R.sub.14, NR.sub.14C(O)NR.sub.14R.sub.14, SR.sub.14, S(O)R.sub.14, S(O).sub.2R.sub.14, CN, haloalkyl, haloalkoxy, C(O)OR.sub.14, C(O)NR.sub.14R.sub.14, OCH.sub.2CH.sub.2OH, NR.sub.14S(O).sub.2NR.sub.14R.sub.14 and C(CH.sub.3).sub.2OR.sub.14;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(629) In a preferred embodiment of the compound according to the invention of general Formula (I) and in relation to the cycloalkyl, aryl or heterocyclyl other than those defined in R.sub.1 or R.sub.2 of any of the embodiments of the present invention,
(630) the cycloalkyl or non-aromatic heterocyclyl, other than those defined in R.sub.1 or R.sub.2, if substituted, may also be substituted with
(631) ##STR00313##
or O;
optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(632) In an embodiment of the compound according to the invention of general Formula (I),
(633) the halogen is fluorine, chlorine, iodine or bromine, preferably fluorine or chlorine;
(634) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(635) In an embodiment of the compound according to the invention of general Formula (I),
(636) the haloalkyl is CF.sub.3;
(637) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(638) In another embodiment of the compound according to the invention of general Formula (I),
(639) the haloalkoxy is OCF.sub.3;
(640) optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
(641) As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the .sub.1 receptor and the -opioid receptor it is a very preferred embodiment in which the compounds are selected which act as dual ligands of the .sub.1 receptor and the -opioid receptor and especially compounds which have a binding expressed as K.sub.i which is preferably <1000 nM for both receptors, more preferably <500 nM, even more preferably <100 nM.
(642) In the following the phrase compound of the invention is used. This is to be understood as any compound according to the invention as described above according to general Formula (I), (I-a), (I-b), (I), (I.sup.2), (I.sup.3), (I.sup.4), (I.sup.5), (I.sup.6), (I.sup.7), (I.sup.8), (I.sup.9), (I.sup.10), (I.sup.11), (I.sup.12), (I.sup.4a) or (I.sup.4b).
(643) The compounds of the invention represented by the above described Formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
(644) In general the processes are described below in the experimental part. The starting materials are commercially available or can be prepared by conventional methods.
(645) A preferred aspect of the invention is also a process for the production of a compound according to Formula (I), following scheme 1.
(646) A preferred aspect of the invention is a process for the production of a compound according to Formula (I), wherein R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X, Y and W are as defined in the description, following scheme 1.
(647) For the sake of clarity the expression a compound according to Formula (I), wherein R.sub.1, etc are as defined in the description would (just like the expression a compound of Formula (I) as defined in, e.g., any one of claims 1 to 10 found in the claims) refer to a compound according to Formula (I), wherein the definitions of the respective substituents R.sub.1 etc. (also from the cited claims) are applied. In addition, this would also mean, though (especially in regards to the claims) that also one or more disclaimers defined in the description (or used in any of the cited claims like e.g. claim 1) would be applicable to define the respective compound. Thus, a disclaimer found in e.g. claim 1 would be also used to define the compound of Formula (I) as defined in any one of claims 1 to 10.
(648) In all processes and uses described underneath and in scheme 1, the values of R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X, Y and W are as defined in the description, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, M is
(649) ##STR00314##
and PG is a protecting group, such as benzyl and tert-butoxycarbonyl. A preferred embodiment of the invention is a process for the production of a compound according to Formula (I), wherein a) when R.sub.1 is C(O)R.sub.1, said process comprises treating a compound of Formula IIb
(650) ##STR00315## with a lithium salt generated from compounds of general formula IIIa
ZR.sub.1 IIIa with organolithium reagent, and hydrolysing the obtained imine intermediate compound to a ketone compound of formula I in the presence of an aqueous inorganic acid, or b) when R.sub.1 is C(R.sub.6R.sub.6).sub.pR.sub.1, said process comprises the reaction of compounds of general formula IIb
(651) ##STR00316## with Grignard reagents of formula IIIb
ZMgR.sub.1 IIIb, or c) said process comprises reacting a compound of general formula VII
(652) ##STR00317## with a compound of general formula VIIIa though an alkylation reaction in the presence of an inorganic or organic base
(653) ##STR00318## or with a compound of general formula VIIIb though a reductive amination reaction in the presence of a reductive agent
(654) ##STR00319##
or with a compound of general formula VIIIc though a condensation reaction
(655) ##STR00320## or d) when W is carbon, said process comprises the reductive alkylation of a cyano derivatives of formula V
(656) ##STR00321## with a compound of formula VIb
(657) ##STR00322## In the presence of lithium naphthalenide.
(658) In a particular embodiment there is a process for the production of a compound of Formula (I) when R.sub.1 is C(O)R.sub.1,
(659) ##STR00323##
said process comprises treating a compound of Formula IIb
(660) ##STR00324##
with a lithium salt generated from compounds of general formula IIIa
ZR.sub.1 IIIa
with an organolithium reagent and hydrolysing the obtained imine intermediate compound to a ketone compound of formula I in the presence of an aqueous inorganic acid.
(661) In a particular embodiment there is a process for the production of a compound of Formula (I) when R.sub.1 is C(R.sub.6R.sub.6).sub.pR.sub.1,
(662) ##STR00325##
said process comprises the reaction of compounds of general formula IIb
(663) ##STR00326##
with Grignard reagents of formula IIIb
ZMgR.sub.1 IIIb.
In a particular embodiment there is a process for the production of a compound of Formula (I),
(664) ##STR00327##
said process comprises reacting a compound of general formula VII
(665) ##STR00328##
with a compound of general formula VIIIa though an alkylation reaction in the presence of an inorganic or organic base
(666) ##STR00329##
(667) In a particular embodiment there is a process for the production of a compound of Formula (I),
(668) ##STR00330##
said process comprises reacting a compound of general formula VII
(669) ##STR00331##
with a compound of general formula VIIIb though a reductive amination reaction in the presence of a reductive agent
(670) ##STR00332##
(671) In a particular embodiment there is a process for the production of a compound of Formula (I),
(672) ##STR00333##
said process comprises reacting a compound of general formula VII
(673) ##STR00334##
with a compound of general formula VIIIc though a condensation reaction
(674) ##STR00335##
(675) In a particular embodiment there is a process for the production of a compound of Formula (I) when W is carbon,
(676) ##STR00336##
said process comprises the reductive alkylation of a cyano derivative of formula V
(677) ##STR00337##
with a compound of formula VIb
(678) ##STR00338##
(679) In the presence of lithium naphthalenide.
(680) In a particular embodiment there is a process for the production of a compound of Formula (IV) when R.sub.1 is C(O)R.sub.1,
(681) ##STR00339##
said process comprises treating a compound of Formula IIa
(682) ##STR00340##
with a lithium salt generated from compounds of general formula IIIa
ZR.sub.1 IIIa
with alkyl lithium, specially n-butyl lithium (nBuLi), and hydrolysing the obtained imine intermediate compound to a ketone compound of formula I in the presence of an aqueous inorganic acid.
(683) In a particular embodiment there is a process for the production of a compound of Formula (IV) when R.sub.1 is C(R.sub.6R.sub.6).sub.pR.sub.1,
(684) ##STR00341##
said process comprises the reaction of compounds of general formula IIa
(685) ##STR00342##
with Grignard reagents of formula IIIb
ZMgR.sub.1 IIIb,
(686) In a particular embodiment there is a process for the production of a compound of Formula (IV) when W is carbon,
(687) ##STR00343##
said process comprises the reductive alkylation of a cyano derivative of formula V
(688) ##STR00344##
with a compound of formula VIa
(689) ##STR00345##
(690) In the presence of lithium naphthalenide.
(691) In a particular embodiment there is a process for the production of a compound of Formula (VII)
(692) ##STR00346##
said process comprises the deprotection of a compound of formula IV
(693) ##STR00347##
(694) In a particular embodiment there is a process for the production of a compound of Formula (IIa), preferably wherein W is carbon,
(695) ##STR00348##
said process comprises the reaction of a compound of formula V
(696) ##STR00349##
with a compound of formula VIa
(697) ##STR00350##
in the presence of a base, preferably lithium diisopropylamide, wherein M is
(698) ##STR00351##
R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in the previous claims, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, and PG is a protecting group.
(699) In a particular embodiment there is a process for the production of a compound of Formula (IIb), preferably wherein W is carbon,
(700) ##STR00352##
said process comprises the reaction of a compound of formula V
(701) ##STR00353##
with a compound of formula VIb
(702) ##STR00354##
in the presence of a base, preferably lithium diisopropylamide, wherein M is
(703) ##STR00355##
R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in the previous claims, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, and PG is a protecting group.
(704) In a particular embodiment there is a process for the production of a compound of Formula (IIa), wherein W is carbon,
(705) ##STR00356##
said process comprises the reaction of a compound of formula IX
(706) ##STR00357##
with a compound of formula Xa
(707) ##STR00358##
in the presence of a base, preferably lithium diisopropylamide, wherein M is
(708) ##STR00359##
(709) R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in the previous claims, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, and PG is a protecting group.
(710) In a particular embodiment there is a process for the production of a compound of Formula (IIb), preferably wherein W is carbon,
(711) ##STR00360##
said process comprises the reaction of a compound of formula IX
(712) ##STR00361##
with a compound of formula Xb
(713) ##STR00362##
in the presence of a base, preferably lithium diisopropylamide, wherein M is
(714) ##STR00363##
(715) R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in the previous claims, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, and PG is a protecting group.
(716) In a particular embodiment there is a process for the preparation of compound of Formula (I), preferably wherein W is carbon, and wherein said compound of Formula (I) is made from intermediate (IIa)
(717) ##STR00364##
obtained from the reaction of a compound of formula V
(718) ##STR00365##
with a compound of formula VIa
(719) ##STR00366##
in the presence of a base, preferably lithium diisopropylamide, or wherein said compound of Formula (I) is made from intermediate (IIb)
(720) ##STR00367##
obtained from the reaction of a compound of formula V
(721) ##STR00368##
with a compound of formula VIb
(722) ##STR00369##
in the presence of a base, preferably lithium diisopropylamide, or wherein said compound of Formula (I) is made from intermediate (IIa)
(723) ##STR00370##
obtained from the reaction of a compound of formula IX
(724) ##STR00371##
with a compound of formula Xa
(725) ##STR00372##
in the presence of a base, preferably lithium diisopropylamide, or
wherein said compound of Formula (I) is made from intermediate (IIb)
(726) ##STR00373##
obtained from the reaction of a compound of formula IX
(727) ##STR00374##
with a compound of formula Xb
(728) ##STR00375##
in the presence of a base, preferably lithium diisopropylamide, wherein M is
(729) ##STR00376##
(730) R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, X and Y are as defined in the previous claims, L is a leaving group such as halogen, mesylate, tosylate or triflate, Z is chloro or bromo, and PG is a protecting group.
(731) The advantages of using the improved processes using intermediates V or IX instead of V are: the synthesis of intermediates IIa and IIb are carried out in one step instead of four. all possible diastereoisomers are easily prepared.
(732) In another particular embodiment a compound of Formula (IIa) or (IIb),
(733) ##STR00377##
is used for the preparation of a compound of Formula (I).
(734) In another particular embodiment a compound of Formula (IIIa),
ZR1 IIIa
is used for the preparation of a compound of Formula (I).
(735) In another particular embodiment a compound of Formula (IIIb),
ZMgR1 IIIb
is used for the preparation of a compound of Formula (I).
(736) In another particular embodiment a compound of Formula (IV),
(737) ##STR00378##
is used for the preparation of a compound of Formula (I).
(738) In another particular embodiment a compound of Formula (V),
(739) ##STR00379##
is used for the preparation of a compound of Formula (I).
(740) In another particular embodiment a compound of Formula (VIa) or (VIb),
(741) ##STR00380##
is used for the preparation of a compound of Formula (I).
(742) In another particular embodiment a compound of Formula (VII),
(743) ##STR00381##
is used for the preparation of a compound of Formula (I).
(744) In another particular embodiment a compound of Formula (VIIIa),
(745) ##STR00382##
is used for the preparation of a compound of Formula (I).
(746) In another particular embodiment a compound of Formula (VIIIb),
(747) ##STR00383##
is used for the preparation of a compound of Formula (I).
(748) In another particular embodiment a compound of Formula (VIIIc),
(749) ##STR00384##
is used for the preparation of a compound of Formula (I).
(750) In another particular embodiment a compound of Formula (V),
(751) ##STR00385##
is used for the preparation of a compound of Formula (I).
(752) In another particular embodiment a compound of Formula (IX),
(753) ##STR00386##
is used for the preparation of a compound of Formula (I).
(754) In another particular embodiment a compound of Formula (Xa),
(755) ##STR00387##
is used for the preparation of a compound of Formula (I).
(756) In another particular embodiment a compound of Formula (Xb),
(757) ##STR00388##
is used for the preparation of a compound of Formula (I).
(758) The obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
(759) One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition. In the case of salts and also solvates of the compounds of the invention the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
(760) Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to general formula I or a pharmaceutically acceptable salt or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
(761) Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
(762) In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
(763) The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
(764) The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
(765) The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
(766) Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
(767) Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
(768) The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
(769) Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament.
(770) Another aspect of the invention refers to a compound of the invention according as described above according to general formula I, or a pharmaceutically acceptable salt or isomer thereof, for use as a medicament for the treatment of pain. Preferably the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.
(771) Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain.
(772) In a preferred embodiment the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.
(773) Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.
(774) The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.
EXAMPLES
General Experimental Part (Methods and Equipment of the Synthesis and Analysis
(775) A process is described in Scheme 1 or Scheme 1 for the preparation of compounds of general formula I, wherein R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4,
(776) R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, W, X and Y have the meanings defined above.
(777) ##STR00389##
(778) ##STR00390##
(779) Where, L is a leaving group such as halogen, mesylate, tosylate or triflate and Z is chloro or bromo, M is the group indicated in a square in Scheme 1 and PG is a protecting group, such as benzyl or tert-butoxycarbonyl.
(780) This process is carried out as described below:
(781) Step 1:
(782) The compounds of general formula IV or I are prepared by reacting a compound of general formula IIa or IIb, with a compound of formula IIIa or IIIb. Depending on the meaning of R.sub.1, different reaction conditions will apply: a) When R.sub.1 is COR.sub.1, compounds of general formula IIa or IIb are treated with a lithium salt in situ generated from compounds of general formula IIIa with nBuLi, in a suitable solvent, preferably in tetrahydrofuran, at a suitable temperature comprised between 78 C. and room temperature, preferably at room temperature. In a subsequent reaction, the obtained imine intermediate compound is hydrolized to ketone compounds of formula IV or I in the presence of an aqueous inorganic acid such as HCl. b) When R.sub.1 is C(R.sub.6,R.sub.6).sub.pR.sub.1, the reaction of compounds of general formula IIa or IIb with Grignard reagents of formula IIIb renders a compound of general formula IV or I. This reaction is carried out in a suitable solvent, preferably in tetrahydrofuran, at a suitable temperature comprised between 0 C. and room temperature.
(783) Additionally, compounds of formula IV or I wherein W is carbon can be obtained by reductive alkylation of cyano derivatives of formula V with compounds of formula VIa or VIb, in the presence of lithium naphthalenide, in a suitable solvent such as tetrahydrofuran, and at a suitable temperature comprised between 40 C. and room temperature.
(784) For compounds of general formula IV, wherein P is a protecting group, two additional steps are necessary to obtain compounds of formula I:
(785) Step 2:
(786) A compound of formula VII is prepared by deprotection of a compound of formula IV. If the protecting group is benzyl the deprotection is carried out under hydrogenation conditions, with hydrogen at a pressure comprised between 1 and 10 bar, in the presence of Pd and in a suitable solvent such as methanol or ethanol, optionally in the presence of an acid such as acetic or hydrochloric acid, at a suitable temperature comprised between room temperature and the reflux temperature. Alternative hydrogenation conditions involve the treatment with dichloroethyl formate as hydrogen source, in a suitable solvent such dichloroethane, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at the reflux temperature. If the protecting group is Boc, the deprotection is carried out in the presence of an inorganic acid such as HCl or trifluoroacetic acid, in a suitable solvent such as dichloromethane, at a suitable temperature comprised between room temperature and the reflux temperature.
(787) Step 3:
(788) From deprotected compounds of formula VII, compounds of general formula I can be prepared by reaction with suitable reagents, such as those of formula VIIIa-c, using different conditions depending on the reagent nature. Thus:
(789) The alkylation reaction with a compound of formula VIIIa is carried out in a suitable solvent, such as acetonitrile, dichloromethane, 1,4-dioxane, ethanol or dimethylformamide, preferably in acetonitrile, in the presence of an inorganic base such as K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3, or an organic base such as triethylamine or diisopropylethylamine, preferably K.sub.2CO.sub.3, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, this reaction can be carried out in a microwave reactor. Additionally, an activating agent such as NaI or KI can be used.
(790) The reductive amination with a compound of formula VIIIb, is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in a suitable solvent, preferably methanol, at a suitable temperature comprised between room temperature and the reflux temperature, preferably in a microwave reactor.
(791) The condensation reaction between a compound of general formula VII and a compound of formula VIIIc is carried out in a suitable solvent, such as ethanol, isopropanol, n-butanol or 2-methoxyethanol, preferably ethanol, optionally in the presence of an organic base such as triethylamine or diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor.
(792) The process described by Steps 1 to 3 represent the general route for the preparation of compounds of formula I. Additionally, the functional groups present in any of the positions can be interconverted using reactions known to those skilled in the art.
(793) Compounds of formula IIa, IIb, IIIa, IIIb, V, VIa, VIb, VIIIa, VIIIb and VIIIc where R.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.4, R.sub.4, R.sub.4, R.sub.5, R.sub.5, R.sub.6, R.sub.6, m, n, p, q, W, Y and X have the meanings as defined above, are commercially available or can be prepared by conventional methods described in the bibliography. Compounds IIa or IIb, wherein W is nitrogen, can be prepared by Strecker reaction of conveniently substituted ketones with amino compounds. The preparation of compounds IIa or IIb wherein W is carbon, involves the treatment of a conveniently substituted nitrile compound with adequate ketones in the presence of a strong base such as LDA, dehydratation of the resulting tertiary alcohol and final reduction of the generated alkene. Additionally, compounds IIa or IIb wherein W is carbon, can be obtained by treatment of cyano derivatives with adequate iodopiperidines in the presence of a strong base, preferably lithium diisopropylamide. Cyano compounds of formula V can be prepared by reaction of conveniently substituted nitriles with suitable R.sub.1CN derivatives in the presence of a strong base.
EXAMPLES
Intermediates and Examples
(794) The following abbreviations are used in the examples:
(795) ACN: Acetonitrile
(796) AcOH: Acetic acid
(797) AcOEt: Ethyl acetate
(798) BINAP: 2,2-Bis(diphenylphosphino)-1,1-binaphthyl
(799) Conc: Concentrated
(800) CH: Cyclohexane
(801) DCM: Dichloromethane
(802) DCE: 1,2-Dicloroethane
(803) DIPEA: N,N-Diisopropylethylamine
(804) DMF: Dimethylformamide
(805) DMPU: N,N-dimetilpropilenourea
(806) DMSO: Dimethyl sulfoxide
(807) EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
(808) EtOH: Ethanol
(809) Et.sub.2O: Diethyl ether
(810) Ex: Example
(811) h: Hour/s
(812) HOBt: Hydroxybenzotriazole
(813) HPLC: High-performance liquid chromatography
(814) INT: Intermediate
(815) LDA: Lithium diisopropilamide
(816) LiHMDS: Lithium bis(trimethylsilyl)amide
(817) MeOH: Methanol
(818) MS: Mass spectrometry
(819) Min: Minutes
(820) Quant: Quantitative
(821) Ret: Retention
(822) rt: Room temperature
(823) Sat: Saturated
(824) TEA: Triethylamine
(825) TFA: Trifluoroacetic acid
(826) THF: Tetrahydrofuran
(827) Wt: Weight
(828) Xamphos: 4, 5-Bis(diphenylphosphino)-9,9-dimethylxanthene
(829) The following methods were used to obtain the HPLC-MS data:
(830) A: Column Acquity UPLC BEH C18 2.150 mm, 1.7 m; flow rate 0.61 mL/min; A: NH.sub.4HCO.sub.3 10 mM; B: ACN; Gradient: 0.3 min in 98% A, 98% A to 5% A in 2.52 min, 1.02 min in 5% A, 5% A to 98% A in 0.34 min, 0.57 min in 98% A
(831) B: Column: Acquity BEH C18 2.150 mm 1.7 m; flow rate 600 l/min; A: NH.sub.4HCO.sub.3 10 mM; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, 0.7 min in 5% A, 5% A to 90% A in 0.1 min, 1.2 min in 90% A
(832) C: Column: Gemini-NX 304.6 mm, 3 um; flow rate: 2.0 mL/min; A: NH.sub.4HCO.sub.3 pH 8; B: ACN; Gradient: 0.5 min in 95% A, 95% A to 0% A in 6.5 min, 1 min in 0% A; 40 C.; sample dissolved aprox. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/can
(833) D: Column Acquity UPLC BEH C18 2.150 mm, 1.7 m; flow rate 0.61 mL/min; A: NH.sub.4HCO.sub.3 10 mM; B: ACN; Gradient: 0.3 min in 98% A, 98% A to 0% A in 2.7 min, 2 min in 0% A, 0% A to 98% A in 0.2 min, 0.55 min in 98% A
(834) E: Column Acquity UPLC BEH C18 2.150 mm, 1.7 m; flow rate 0.5 mL/min; A: NH.sub.4HCO.sub.3 10 mM; B: ACN; Gradient: 90% A to 5% A in 4 min, 1 min in 5% A, 5% A to 90% A in 0.1 min, 1.9 min in 90% A
Intermediate 1A. 4-(4-Benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile
(835) ##STR00391##
(836) In a 2 L round bottomed flask, 2,2-dimethyldihydro-2H-pyran-4(3H)-one (10.4 g, 0.08 mol) was dissolved in water (500 mL) along with sodium metabisulfite (7.7 g, 0.04 mol). The mixture was allowed to stir at rt for 1.5 h, then benzylpiperazine (14.2 g, 0.08 mol) was added. The mixture was stirred for 2 h and potassium cyanide (8.42 g, 0.13 mol) was added to the reaction mixture. After stirring at rt for 2 days the solid formed was filtered and dried, to give the title compound as a white solid (15.4 g, yield 61%).
(837) HPLC-MS (Method A): Ret, 1.98 min; ESI.sup.+-MS m/z, 314.1 (M+1).
(838) This method was used for the preparation of intermediates 1B-O using suitable starting materials:
(839) TABLE-US-00004 Chemical Ret MS INT Structure name Method (min) (M + H) 1B
Intermediate 1P. 4-(1-Benzylpiperidin-4-yl)tetrahydro-2H-pyran-4-carbonitrile
(840) ##STR00406##
a) tert-Butyl-4-(4-cyanotetrahydro-2H-pyran-4-yl)-4-hydroxypiperidine-1 carboxylate
(841) To a solution of tetrahydro-2H-pyran-4-carbonitrile (4.85 g, 43.6 mmol) in dry THF (41 mL), cooled at 78 C., a LDA solution (30.5 mL, 1.5 M in a mixture of THF/ethylbenzene/heptane, 45.8 mmol) was added dropwise under a nitrogen atmosphere. The mixture was stirred at 50 C. for 45 min and then it was cooled at 78 C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (8.69 g, 43.6 mmol) in dry THF (5.2 mL) was added and the reaction mixture was stirred at 78 C. for 2 h. Then, NH.sub.4Cl sat aqueous solution was added and the mixture was extracted with EtOAc. The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:9) to give the title compound (7.11 g, 53% yield).
(842) HPLC-MS (Method C): Ret, 3.18 min; ESI.sup.+-MS m/z, 255 (M+H-56).
b) tert-Butyl 4-(4-cyanotetrahydro-2H-pyran-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate
(843) To a solution of the product obtained in step a (6.10 g, 19.7 mmol) in toluene (71 mL), (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent, 7.03 g, 29.5 mmol) was added and the mixture was heated at 90 C. overnight under a nitrogen atmosphere. It was then cooled to rt and water and DCM were added. The aqueous phase was back extracted with DCM. The organic phases were combined, washed with sat NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to give the title compound (6.14 g crude product, 5.75 g theoretical weight; quant yield).
(844) HPLC-MS (Method C): Ret, 3.91 min; ESI.sup.+-MS m/z, 237.1 (M+H-56).
c) tert-Butyl 4-(4-cyanotetrahydro-2H-pyran-4-yl)piperidine-1-carboxylate
(845) A mixture of the crude product obtained in step b (6.14 g crude, 19.7 mmol) and palladium (1.23 g, 5% wt on charcoal, wet) in EtOH (115 mL) was stirred at rt under 1 bar of H.sub.2 overnight. Then, the solids were filtered off over a pad of celite and the solvent was evaporated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:9) to give the title compound (4.04 g, 70% yield).
(846) HPLC-MS (Method C): Ret, 3.79 min; ESI.sup.+-MS m/z, 239.1 (M+H-56).
d) 4-(Piperidin-4-yl)tetrahydro-2H-pyran-4-carbonitrile trifluoroacetate
(847) To a solution of the product obtained in step c (4.0 g, 13.6 mmol) in DCM (40 mL), TFA (10.4 mL, 136 mmol) was added, and the reaction mixture was stirred at rt. for 1 h. The solvent was evaporated to dryness to give the title compound as a crude product (7.18 g, 4.19 g theoretical weight, quant yield), that was used in the following step without further purification.
(848) HPLC-MS (Method C): Ret, 0.98 min (peak corresponds to TIC spectrum, no peak detected in UV detector at 210 nm) ESI-MS m/z, 195.1 (M+H).
e) Title Compound
(849) To a solution of the crude product obtained in step d (7.18 g crude, 13.6 mmol) and benzaldehyde (1.3 mL, 17.7 mmol) in dry THF (92 mL), AcOH (1.73 mL, 30.2 mmol) was added. The mixture was stirred at rt for 15 min and then sodium triacetoxyborohydride (7.99 g, 40.8 mmol) was added in portions. The resulting mixture was stirred at rt overnight. Then, conc. NH.sub.4OH (50 mL) was carefully added and it was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (1.75 g, 45% yield).
(850) HPLC-MS (Method C): Ret, 3.83 min; ESI-MS m/z, 252.2 (M+H).
(851) This method was used for the preparation of INT 1Q using suitable starting materials:
(852) TABLE-US-00005 Chemical Ret MS INT Structure name Method (min) (M + H) 1Q
Alternative Method for the Obtention of Intermediate 1Q. 4-(1-benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile
(853) ##STR00408##
(854) To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (800 mg, 5.7 mmol) in dry THF (15 mL) cooled at 0 C., a solution of lithium diisopropylamide (2 M in THF, 4.02 mL, 8 mmol) was added dropwise under nitrogen atmosphere. The mixture was stirred at rt temperature for 40 min. Then it was cooled down again to 0 C., and a solution of 1-benzyl-4-iodopiperidine (1.73 g, 5.7 mmol) in dry THF (15 mL) and DMPU (3.1 mL, 25.6 mmol) was added. The reaction mixture was allowed to reach rt and stirred overnight. The solvent was evaporated and the residue was diluted with water and AcOEt, extracted several times and the organic phases were combined and washed with NaHCO.sub.3 aq sat solution. The solvent was evaporated and the residue thus obtained was purified by flash chromatography on silica gel, gradient DCM to DCM:MeOH (80:20) from 0 to 10% to give the title compound (800 mg, 45% yield).
(855) HPLC-MS (Method B): Ret, 2.05 min; ESI.sup.+-MS m/z, 312.3 (M+H).
(856) This method was used for the preparation of intermediate 1R using the suitable tetrahydropyran derivative as starting material:
(857) TABLE-US-00006 Chemical Ret MS INT Structure name Method (min) (M + H) 1R
Intermediate 1S. 4-(1-Benzylpiperidin-4-yl)-2-methyltetrahydro-2H-pyran-4-carbonitrile (Diastereomeric Mixture)
(858) ##STR00410##
(859) To a solution of 2-(1-benzylpiperidin-4-yl)acetonitrile (300 mg, 1.4 mmol) in THF (40 mL), a solution of LDA (2.8 mL, 4.2 mmol, 1.5 M in THF) was added dropwise at 0 C. and the mixture allowed to stir at rt for 40 min. Then, a solution of 1-iodo-2-(2-iodoethoxy)propane (500 mg, 1.47 mmol) in THF (20 mL) and DMPU (0.6 mL, 3.5 mmol) were added at 0 C. and the mixture was allowed to slowly reach rt and stirred for 16 h. The solvent was removed under vacuum and the crude product was extracted with EtOAc, washed with NH.sub.4Cl and with a solution of NaHCO.sub.3. The organic layer was concentrated under vacuum and the crude was purified by flash chromatography on silica gel (eluents Cyclohexane/EtOAc from 90/10 to 0/100). The title compound (63 mg, yield 15%) was isolated as a mixture of four diastereomers (two chromatographic peaks).
(860) HPLC-MS (Method B): Diastereomers 1: Ret, 2.07 min; ESI.sup.+-MS m/z, 299 (M+H). Diastereomers 2: Ret, 2.14 min; ESI.sup.+-MS m/z, 299 (M+H).
(861) Intermediates 1T-1Y were prepared according to the procedure described in intermediate 1A using suitable starting materials
(862) TABLE-US-00007 Chemical INT Structure name .sup.1H NMR 1T
Intermediate 2A. 2-(2,2-Dimethyl-4-(piperidin-4-yl)tetrahydro-2H-pyran-4-yl)pyridine
(863) ##STR00417##
a) 2,2-Dimethyl-4-(pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile
(864) To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (1.82 g, 13.1 mmol) and 2-cyanopyridine (1.36 g, 13.1 mmol) in dry THF (9 mL), cooled at 78 C., LiHMDS solution (14.4 mL, 1 M in THF, 14.4 mmol) was added dropwise under a nitrogen atmosphere. The mixture was then stirred at rt for 2 hours. NH.sub.4Cl sat aqueous solution was added and it was extracted 3 times with EtOAc. The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient Cyclohexane to EtOAc (9:1) to give the title compound (2.02 g, 71% yield).
(865) HPLC retention time (method C): 3.11 min; MS: 217.1 (M+H).
b) tert-Butyl 4-(2,2-dimethyl-4-(pyridin-2-yl)tetrahydro-2H-pyran-4 yl)piperidine-1-carboxylate
(866) To a solution of the product obtained in step a (0.4 g, 1.85 mmol) in dry THF (18.5 mL), cooled at 40 C., lithium naphthalenide solution (11.1 mL, 0.5 M in THF, 5.55 mmol; prepared as described in Tetrahedron Lett. 1997, 38, 2253) was added dropwise under an argon atmosphere and it was stirred at 40 C. for 40 min. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (2.3 g, 7.4 mmol) in dry THF (5 mL) was added at 40 C. and the mixture was further stirred at 40 C. for 1 h and then at rt overnight. NH.sub.4Cl sat aqueous solution was added and it was extracted 3 times with DCM. The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:9) and then further purified by flash chromatography, C.sub.18, gradient aqueous NH.sub.4HCO.sub.3 (pH 8) to acetonitrile to give the title compound (190 mg, 27% yield).
(867) HPLC retention time (method A): 4.57 min; MS: 375.2 (M+H).
c) Title Compound
(868) Boc deprotection was effected following the procedure described in INT 1P step d.
(869) HPLC retention time (method A): 2.22 min; MS: 275.2 (M+H).
(870) This method was used for the preparation of INT 2B using suitable starting materials:
(871) TABLE-US-00008 Chemical Ret MS INT Structure name Method (min) (M + H) 2B
Example 1. (4-(4-Benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(872) ##STR00419##
a) (4-(4-Benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanimine
(873) 2-Bromopyridine (4.6 mL, 0.048 mol) in THF, under argon atmosphere, was cooled down to 78 C. and at this temperature n-BuLi (1.6 M, 31 mL, 0.049 mol) was added. The reaction was kept for 30 min at this temperature and a solution of 4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (INT 1A, 5 g, 0.016 mol.) in THF was added. The reaction was slowly allowed to reach rt. and stirred overnight. The mixture was quenched with NH.sub.4Cl and extracted with ether. The combined organic fractions were dried over sodium sulphate. The solvent was removed under reduced pressure after filtration, to give the crude title compound as an oil, that was used in the following step without further purification.
(874) HPLC-MS (Method A): Ret, 1.97 min; ESI.sup.+-MS m/z, 394.3 (M+1).
b): Title Compound
(875) The crude imine obtained in step a (6.3 g, 0.02 mol) was dissolved in THF (250 mL) and 3N HCl (ca. 124 mL) was added. The reaction was stirred until full conversion to ketone was achieved (HPLC analysis). The mixture was made alkaline with 10% NaOH and extracted twice with ether. The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a brown oil. The crude was purified by flash chromatography on silica gel, eluents CH:AcOEt, gradient to 80:20 to give the title compound (4.7 g, yield 75% over two steps).
(876) HPLC-MS (Method A): Ret, 2.29 min; ESI.sup.+-MS m/z, 394.3 (M+1).
Examples 2 and 3. (R) and (S) (4-(4-Benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(877) The enantiomers of Ex 1 were separated by preparative HPLC using Chiralpak AS-H Column, flow rate 12 mL/min A: n-Heptano; B: (IPA+0.33% DEA) 98/2 v/v, rt to give:
(878) TABLE-US-00009 Chemical Ret MS EX Structure name Method (min) (M + H) 2
Examples 4-22
(879) Examples 4-22 were prepared using the method described for the preparation of example 1 and using the corresponding intermediates 1A-1Q as starting materials:
(880) TABLE-US-00010 Chemical Ret MS EX Structure name Method (min) (M + H) 4
(881) Examples 27 and 28. (2S,4R) and (2R,4S) 4-(4-Benzylpiperazin-1-yl)-2-methyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone.
(882) The enantiomers of example 25 were separated by preparative HPLC using Chiralpak IC Column, flow rate 12 mL/min A: n-Heptane; B: (EtOH+0.33% DEA) 90/10 v/v, rt to give examples 27 and 28:
(883) TABLE-US-00011 Chemical Ret MS EX Structure name Method (min) (M + H) 27
Example 29. 1-Benzyl-4-(9-ethyl-6-oxaspiro[4.5]decan-9-yl)piperazine
(884) ##STR00447##
(885) A solution of 9-(4-benzylpiperazin-1-yl)-6-oxaspiro[4.5]decane-9-carbonitrile (INT 1 D, 70 mg, 0.206 mmol) in THF (3 mL) was cooled down to 0 C. and ethylmagnesium bromide (3M in ethyl ether, 206 L, 0.619 mmol) was added. The resulting mixture was allowed to warm up and stirred at room temperature overnight under argon atmosphere. The reaction was quenched by addition of sat solution of NH.sub.4Cl. The product was extracted with EtOAc and the combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give the title compound as yellow oil (70 mg, yield 96%)
(886) HPLC-MS (Method A): Ret, 2.72 min; ESI.sup.+-MS m/z, 343.3 (M+1).
(887) This method was used for the preparation of examples 30-47 using the adequate magnesium reagents and the corresponding intermediates 1 as starting materials.
(888) TABLE-US-00012 Chemical Ret MS Ex Structure name Method (min) (M + H) 30
Example 48. 2-(2,2-Dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)ethanol
(889) ##STR00466##
(890) 1-(2,2-Dimethyl-4-vinyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine (Ex 45, 340 mg, 1.03 mmol) was dissolved in THF (30 mL) under argon atmosphere in a Schlenk tube. Then, a 9-BBN solution (7.76 mL, 3.1 mmol) was added dropwise and the reaction mixture was stirred overnight at rt. The reaction was cooled down to 0 C. and NaOH (10%, 2 mL) was added, followed by a H.sub.2O.sub.2 solution (30%, 1 mL) and the reaction stirred at r.t. for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (3). The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give an oil was purified by flash chromatography on silica gel (eluents DCM:MeOH), to give the title compound (135 mg, yield 38%).
(891) HPLC-MS (Method E): Ret, 3.5 min; ESI.sup.+-MS m/z, 347.3 (M+1).
Example 49. 1-(4-(2-Methoxyethyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine
(892) ##STR00467##
(893) To a solution of 2-(2,2-dimethyl-4-(4-phenethylpiperazin-1-yl)tetrahydro-2H-pyran-4-yl)ethanol (Ex. 48, 46 mg, 1.13 mmol) in anhydrous DMF (1 mL) NaH (60% in mineral oil, 17 mg, 0.4 mmol) was added and the suspension was stirred at rt for 20 min. Then, Me.sub.2SO.sub.4 (37 l, 0.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and aqueous sat NaHCO.sub.3 solution extracted with EtOAc and washed twice with aqueous sat NaCl solution. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (eluents DCM:MeOH gradient to 90:10), to give the title compound as a colorless oil (4 mg, yield 8%).
(894) HPLC-MS (Method D): Ret, 2.13 min; ESI.sup.+-MS m/z, 361.3 (M+1).
Example 50. (2,2-Dimethyl-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(895) ##STR00468##
a) (2,2-Dimethyl-4-(piperazin-1-yl)tetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone hydrochloride
(896) To a solution of (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone (Ex 1, 1.05 g, 2.67 mmol) in DCM (75 mL), dichloroethyl formate (600 L, 5.561 mmol) was added and the reaction mixture heated to reflux for 3 h. After cooling down to rt, all volatiles were removed under reduced pressure. MeOH was then added and the reaction mixture heated again to reflux for 2 h. After cooling back to rt, the solvent was removed and the brown solid thus obtained was washed several times with ether and dried in vacuo (712 mg, yield 73%).
(897) HPLC-MS (Method A): Ret, 1.12 min; ESI.sup.+-MS m/z, 304.1 (M+1).
b) Title Compound
(898) 2-(Bromomethyl)pyridine hydrochloride (97 mg, 0.47 mmol) was added to a solution of the compound obtained in step a (106 mg, 0.31 mmol) and K.sub.2CO.sub.3 (215 mg, 1.56 mmol) in ACN (8 mL). The reaction mixture was stirred at 65 C. overnight and then it was cooled down to rt. AcOEt (10 mL) and sat aqueous NaHCO.sub.3 solution (10 mL) were added and the phases were separated. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (eluents DCM:MeOH gradient to 80:20), to give the title compound as an oil (72 mg, yield 60%).
(899) HPLC-MS (Method A): Ret, 1.82 min; ESI.sup.+-MS m/z, 395.2 (M+1).
(900) This method was used for the preparation of examples 51-111 using the adequate alkylating agents and the corresponding benzyl examples or INT 2 as starting materials.
(901) TABLE-US-00013 Ret MS EX Structure Chemical name Method (min) (M + H) 51
Examples 112 and 113. (S) and (R) 1-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenethylpiperazine
(902) ##STR00530##
(903) Examples 112 and 113 were obtained by chiral preparative HPLC from example 52.
(904) Column: Chiralpak IA; Temperature: ambient; Flow: 13 mL/min; Mobile phase: n-Heptane/(EtOH+0.33% DEA) 97/3 v/v.
(905) Example 112 HPLC-MS (Method D): Ret, 2.39 min; ESI.sup.+-MS m/z, 331.3 (M+1).
(906) Example 113 HPLC-MS (Method D): Ret, 2.39 min; ESI.sup.+-MS m/z, 331.3 (M+1).
Examples 114 and 115. (S) and (R) (4-(1-isopentylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(907) ##STR00531##
(908) Examples 114 and 115 were obtained by chiral preparative HPLC from example 76.
(909) Column: Chiralpak AD-H; Temperature: ambient; Flow: 11 mL/min; Mobile phase: n-Heptane/(EtOH+0.33% DEA) 98/2 v/v.
(910) Example 114 HPLC-MS (Method D): Ret, 2.12 min; ESI.sup.+-MS m/z, 373.3 (M+1).
(911) Example 115 HPLC-MS (Method D): Ret, 2.12 min; ESI.sup.+-MS m/z, 373.3 (M+1).
Example 116. (4-(4-(2-(2-Fluoro-2-methylpropoxy)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(912) ##STR00532##
(913) Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride, 50% in toluene, 132 L) was added dropwise at 0 C. to a solution of (4-(4-(2-(2-hydroxy-2-methylpropoxy)ethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone (Example 70, 65 mg, 0.15 mmol) in toluene (4 mL). The mixture was stirred for 1 h at 0 C. and at rt overnight. Then, the solvent was concentrated in vacuo and the residue was partitioned between DCM and 0.1 N NaOH solution. The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by preparative HPLC (column X-Bridge C18, ACN: NH.sub.4HCO.sub.3 10 mM from (2:98 to 95-5), flow 20 ml/min, rt) to give the title compound (14 mg, yield 17%).
(914) HPLC-MS (Method A): Ret, 1.99 min; ESI.sup.+-MS m/z, 422.2 (M+1).
(915) This method was used for the preparation of example 117 using example 90 as starting material. Example 118 was also isolated.
(916) TABLE-US-00014 Chemical Ret MS Ex Structure name Method (min) (M + H) 117
Example 119. 1-(9-Phenyl-6-oxaspiro[4.5]decan-9-yl)-4-(pyridin-3-ylmethyl)piperazine
(917) ##STR00535##
a) 1-(9-Phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine
(918) The title compound was obtained following the procedure described in Ex 50 step a, using 1-benzyl-4-(9-phenyl-6-oxaspiro[4.5]decan-9-yl)piperazine (Ex 26) as starting material.
(919) HPLC-MS (Method A): Ret, 1.51 min; ESI.sup.+-MS m/z, 301.2 (M+1).
b) Title Compound
(920) The compound obtained in step a (18 mg, 0.06 mmol) was introduced in a process vial, under argon atmosphere, and dissolved in MeOH (2 mL). Nicotinaldehyde (19 mg, 0.18 mmol) and sodium triacetoxyborohydride (15 mg, 0.24 mmol) were added, and the vial was sealed with a septum. The suspension was subjected to microwave irradiating conditions for 30 min at 120 C. and then cooled. The crude product was evaporated to dryness and then suspended in aqueous NaHCO.sub.3. The mixture was extracted with DCM and washed with sat aqueous NaHCO.sub.3 solution. The organic layer was dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography on silica gel, gradient DCM to DCM:MeOH (70:30), to afford the title compound (3 mg, yield 10%).
(921) HPLC-MS (Method A): Ret, 2.12 min; ESI.sup.+-MS m/z, 392.3 (M+1).
(922) This method was used for the preparation of examples 120-128 using suitable aldehydes or ketones and the corresponding benzyl examples or INT 2 as starting materials:
(923) TABLE-US-00015 Chemical Ret MS Ex Structure name Method (min) (M + H) 120
Example 129. (4-(4-Benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanol
(924) ##STR00545##
(925) To a solution of (4-(4-benzylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone (Ex 1, 161 mg, 0.409 mmol) in EtOH (10 mL), sodium tetrahydroborate (31 mg, 0.818 mmol) was added at 0 C. The reaction was stirred at rt for 2 h, it was quenched with water and stirred at rt for 2 days. Then, DCM was added and the aqueous layer was separated and extracted several times with DCM. The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound as a solid (140 mg, 86% yield).
(926) HPLC-MS (Method B): Ret, 2.19 min; ESI.sup.+-MS m/z, 396.2 (M+1).
(927) This method was used for the preparation of Ex 130-131 using the corresponding examples 21 and 22 as starting materials:
(928) TABLE-US-00016 Ret MS Ex Structure Chemical name Method (min) (M + H) 130
Examples 132 and 133. (S) and (R) (4-(4-isopentylpiperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(929) ##STR00548##
(930) Examples 132 and 133 were obtained by chiral preparative HPLC from example 64.
(931) Column: Chiralpak IA; Temperature: ambient; Flow: 12 mL/min; Mobile phase: n-Heptane/(EtOH+0.33% DEA) 90/10 v/v.
(932) Example 75 HPLC-MS (Method A): Ret, 2.27 min; ESI.sup.+-MS m/z, 374.2 (M+1).
(933) Example 76 HPLC-MS (Method A): Ret, 2.27 min; ESI.sup.+-MS m/z, 374.2 (M+1).
(934) This method was used for the preparation of Ex 134 and 135 using example 65 as starting material:
(935) TABLE-US-00017 Ret MS Ex Structure Chemical name Method (min) (M + H) 134
Examples 136 and 137. (S) and (R) (4-(4-(2-isobutoxyethyl)piperazin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(936) ##STR00551##
(937) Examples 136 and 137 were obtained by chiral preparative HPLC from example 66.
(938) Column: Chiralpak IC; Temperature: ambient; Flow: 12 mL/min; Mobile phase: n-Heptane/(IPA+0.33% DEA) 90/10 v/v.
(939) Example 79 HPLC-MS (Method A): Ret, 2.22 min; ESI.sup.+-MS m/z, 404.2 (M+1).
(940) Example 80 HPLC-MS (Method A): Ret, 2.22 min; ESI.sup.+-MS m/z, 404.2 (M+1).
Example 138. (4-((S)-3-(Benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(941) ##STR00552##
a) (S) tert-Butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate
(942) Et.sub.3N (5.58 mL, 40 mmol) was added to a solution of (S) tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3 g, 16.02 mmol) in dry DCM (35 mL). The solution was cooled to 0 C., stirred for 10 min and then, methanesulfonyl chloride (2.1 mL, 27.24 mmol) was added and the reaction mixture was stirred at 0 C. After 1 h the reaction mixture was allowed to warm to rt and stirred for 0.5 h. The mixture was poured into ice-water and diluted with DCM. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to afford the title compound as a crude yellow oil (4.25 g) that was used in the next step without further purification.
(943) .sup.1H NMR (400 MHz, CDC13) ppm 1.49 (s, 9H) 2.08-2.21 (m, 1H) 2.29 (br. s., 1H) 3.07 (s, 3H) 3.36-3.64 (m, 3H) 3.65-3.75 (m, 1H) 5.28 (tt, J=4.23, 2.08 Hz, 1H))
b) (S) tert-Butyl 3-(benzyl(methyl)amino)pyrrolidine-1-carboxylate
(944) A mixture of the compound obtained in step a (4.25 g, 16.02 mmol)) and N-methyl-1-phenylmethanamine (6.20 mL, 48.07 mmol) was stirred and heated at 100 C. for 3 h, under nitrogen. The residue was partitioned between DCM/water. The aqueous phase was further extracted with dichloromethane. The combined extracts were washed with brine, dried (Na.sub.2SO.sub.4) filtered and evaporated. The crude product thus obtained was purified by flash chromatography on silica gel, gradient CH:AcOEt from (100:0) to (70:30) to give the title compound as yellow oil (2.93 g, 63% yield).
(945) HPLC-MS (Method A): Ret, 2.20 min; ESI.sup.+-MS m/z, 291 (M+1).
c) (S) N-Benzyl-N-methylpyrrolidin-3-amine
(946) Over a suspension of (the compound obtained in step b (2.5 g, 8.71 mmol) in DCM (20 mL), TFA (16.7 mL, 218 mmol) was added and the mixture was stirred at rt for 1 h. The solvent was concentrated off and the crude residue was diluted with H.sub.2O (30 mL), taken up to pH 12 with 10% aqueous NaOH solution and extracted with DCM (30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound as brown oil (1.66 g, quant yield).
(947) HPLC-MS (Method A): Ret, 1.01 min; ESI.sup.+-MS m/z, 191 (M+1).
d) 4-((S)-3-(Benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile
(948) The title compound was obtained following the procedure described in INT 1, using compound obtained in step c as starting material.
e) Title Compound
(949) The title compound was obtained following the procedure described in Ex 1, using compound obtained in step d as starting material.
(950) HPLC-MS (Method A): Ret, 2.33 min; ESI.sup.+-MS m/z, 408.2 (M+1).
(951) This method was used for the preparation of example 139 using (R) tert-butyl 3-hydroxypyrrolidine-1-carboxylate as starting material.
(952) TABLE-US-00018 Ret MS Ex Structure Chemical name Method (min) (M + H) 139
Examples 140 and 141. ((S)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone and ((R)-4-((S)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(953) The diastereoisomers of example 138 were separated by preparative HPLC using Chiralpak IC Column, flow rate 12 mL/min A: n-Heptane B: (IPA+0.33% DEA) 95/5 v/v, rt to give:
(954) TABLE-US-00019 Ret MS Ex Structure Chemical name Method (min) (M + H) 140
Examples 142 and 143. ((R)-4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone and ((S)-4-((R)-3-(benzyl(methyl)amino)pyrrolidin-1-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)(pyridin-2-yl)methanone
(955) The diastereoisomers of example 139 were separated by preparative HPLC using Chiralpak IC Column, flow rate 12 mL/min A: n-Heptano; B: (IPA+0.33% DEA) 95/5 v/v, rt to give:
(956) TABLE-US-00020 Ret MS Ex Structure Chemical name Method (min) (M + H) 142
(957) Examples 144-155 were prepared according to the procedure described in example 1, using suitable intermediates 1 as starting materials. The compounds were obtained as diastereomeric mixtures or racemates, and were separated by preparative HPLC to give the final examples. HPLC conditions were: Chiralpak IC Column, flow rate 10 or 11 or 12 mL/min, A: n-Heptane B: (IPA+0.33% DEA) 95/5 v/v or A: ACN B: (IPA+5% DEA) 98/2 v/v or A: n-Heptane B: (EtOH+0.33% DEA) 90/10 v/v rt. For examples 146 and 147, the conditions were: Lux C4 column, flow rate 21 mL/min, A: ACN B: (IPA+0.1% NH3) 90/10 v/v, rt.
(958) TABLE-US-00021 Ret MS Ex Structure Chemical name Method (min) (M + H) 144
(959) Examples 156-166 were prepared according to the procedure described in example 29, using suitable intermediates 1 as starting materials.
(960) TABLE-US-00022 Chemical Ret MS Ex Structure name Method (min) (M + H) 156
Example 167. 1-Benzyl-4-(4-ethyl-2,2-dimethyltetrahydro-2H-pyran-4-yl)piperidine
(961) ##STR00581##
a) 1-(4-(1-Benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanimine
(962) 4-(1-Benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (INT 1Q, 375 mg, 1.2 mmol) was dissolved in THF, under argon atmosphere and cooled down to 0 C. At this temperature methyllithium (1.6 M in ether, 7.5 mL, 12 mmol) was added. The reaction was slowly allowed to reach rt. and stirred overnight. The mixture was quenched with NH.sub.4Cl and volatiles were removed under vacuum. The crude residue was extracted with AcOEt, dried over sodium sulphate, filtered and concentrated to give a crude product that was used in following step without further purification (337 mg, 68% purity, yield 58%).
(963) HPLC-MS (Method A): Ret 2.04 min; ESI.sup.+-MS m/z, 329 (M+1).
b) 1-(4-(1-Benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanone
(964) The crude imine obtained in step a (337 mg, 0.7 mmol) was dissolved in THF (10 mL) and 3 N HCl (ca. 4 mL) was added. The reaction mixture was stirred until full conversion to ketone was achieved (HPLC analysis). The mixture was made alkaline with 10% NaOH and extracted twice with AcOEt. The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel, eluents DCM/MeOH, from 0 to 35% MeOH, to give the title compound (210 mg, yield 91%).
(965) HPLC-MS (Method A): Ret, 2.38 min; ESI.sup.+-MS m/z, 330 (M+1).
c) 1-(4-(1-Benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)ethanol
(966) A solution of LiAlH.sub.4 (1M in THF, 1.9 mL, 1.9 mmol) was added dropwise at 0 C. to a solution of the compound obtained in step b (210 mg, 0.64 mmol), in dry THF (6 mL). The mixture was allowed to reach rt and stirred overnight. Then, the solution was quenched with NaOH (2.5 M, 2 mL) at 0 C., filtered and washed with more THF (410 mL). The filtrate was evaporated to dryness to give the title compound (203 mg, yield 96%).
(967) HPLC-MS (Method A): Ret, 2.08 min; ESI.sup.+-MS m/z, 332 (M+1).
d) O-(1-(4-(1-Benzylpiperidin-4-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl) 1H-imidazole-1-carbothioate
(968) In a kimax tube, a solution of the compound obtained in step c, obtained in step c (200 mg, 0.6 mmol), thiocarbonyldiimidazolide (323 mg, 1.8 mmol), and 4-(dimethylamino)pyridine (22 mg, 0.18 mmol) in a minimum amount of ether was evaporated to dryness. The resulting solid was heated at 50-55 C. for 2.5 h under nitrogen atmosphere. Then, the residue was purified by column chromatography, DCM/MeOH, from 0 to 10% to give the title compound (203 mg, yield 76%).
(969) HPLC-MS (Method A): Ret, 2.84 min; ESI.sup.+-MS m/z, 442.6 (M+1).
e) Title Compound
(970) To a solution of the compound obtained in step d (180 mg, 0.41 mmol) and (E)-3,3-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 7 mg, 0.04 mmol) in anh. Toluene (5 mL), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane ((TMS).sub.3SiH, 0.6 mL, 2 mmol) was added. The solution was fully degassed with Ar and it was refluxed for 4 h. Volatiles were removed under vacuum. The residue was extracted in EtOAc (50 mL), washed with aq sat NaHCO.sub.3 solution and the organic layer was dried and concentrated under vacuum. The crude product was purified by column chromatography in DCM/MeOH, from 0 to 50% to give title compound (117 mg, yield 90%).
(971) HPLC-MS (Method A): Ret, 2.53 min; ESI.sup.+-MS m/z, 316.2 (M+1).
(972) Examples 168-239 were prepared according to the procedure described in example 50, using the adequate alkylating agents and the corresponding benzyl examples as starting materials
(973) TABLE-US-00023 Ret MS Ex Structure Chemical name Method (min) (M + H) 168
Examples 240-251
(974) The enantiomers of racemic compounds in examples 26, 74, 77, 168, 172 and 186 were separated by preparative HPLC using Chiralpak IC Column, flow rates 10 or 11 or 12 mL/min A: n-Heptane B: (IPA+0.33% DEA) 70/30 or A: n-Heptane B: (EtOH+5% DEA) 95/5 v/v or A: n-Heptane B: (EtOH+0.33% DEA) 95/5 v/v or A: n-Heptane B: (EtOH+0.33% DEA) 90/10 v/v, rt to give:
(975) TABLE-US-00024 Ret MS Ex Structure Chemical name Method (min) (M + H) 240
Table of Examples with Binding to the -Opioid Receptor and the .sub.1-Receptor:
BIOLOGICAL ACTIVITY
(976) Pharmacological Study
(977) Human .sub.1 Receptor Radioligand Assay
(978) To investigate binding properties of test compounds to human .sub.1 receptor, transfected HEK-293 membranes and [.sup.3H](+)-pentazocine (Perkin Elmer, NET-1056), as the radioligand, were used. The assay was carried out with 7 g of membrane suspension, 5 nM of [.sup.3H](+)-pentazocine in either absence or presence of either buffer or 10 M Haloperidol for total and non-specific binding, respectively. Binding buffer contained Tris-HCl 50 mM at pH 8. Plates were incubated at 37 C. for 120 minutes. After the incubation period, the reaction mix was then transferred to MultiScreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris-HCL (pH7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail
(979) Human -Opioid Receptor Radioligand Assay
(980) To investigate binding properties of test compounds to human -opioid receptor, transfected CHO-K1 cell membranes and [.sup.3H]-DAMGO (Perkin Elmer, ES-542-C), as the radioligand, were used. The assay was carried out with 20 g of membrane suspension, 1 nM of [.sup.3H]-DAMGO in either absence or presence of either buffer or 10 M Naloxone for total and non-specific binding, respectively. Binding buffer contained Tris-HCl 50 mM, MgCl2 5 mM at pH 7.4. Plates were incubated at 27 C. for 60 minutes. After the incubation period, the reaction mix was then transferred to MultiScreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris-HCL (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.
(981) Results:
(982) As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the .sub.1 receptor and the -opioid receptor it is a very preferred embodiment in which the compounds are selected which act as dual ligands of the .sub.1 receptor and the -opioid receptor and especially compounds which have a binding expressed as K.sub.i which is preferably <1000 nM for both receptors, more preferably <500 nM, even more preferably <100 nM.
(983) The following scale as been adopted for representing the binding to the .sub.1 receptor and the -opioid receptor expressed as K.sub.i: + Both K.sub.i- and K.sub.i-.sub.1>=500 nM ++ One K.sub.i<500 nM while the other K.sub.i is >=500 nM +++ Both K.sub.i- and K.sub.i-.sub.1<500 nM ++++ Both K.sub.i- and K.sub.i-.sub.1<100 nM
(984) All compounds prepared in the present application exhibit binding to the .sub.1 receptor and the -opioid receptor, in particular the following binding results are shown:
(985) TABLE-US-00025 and .sub.1 dual EX binding 1 ++++ 2 ++ 3 ++++ 4 ++++ 5 ++++ 6 ++++ 7 ++++ 8 ++ 9 ++ 10 ++ 11 ++ 12 +++ 13 ++ 14 + 15 ++++ 16 +++ 17 ++ 18 +++ 19 ++ 20 ++ 21 ++ 22 +++ 23 + 24 +++ 25 + 26 +++ 27 +++ 28 ++ 29 +++ 30 ++ 31 ++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 ++ 37 ++ 38 ++ 39 ++ 40 ++++ 41 +++ 42 ++++ 43 +++ 44 +++ 45 + 46 ++ 47 ++ 48 + 49 +++ 50 ++ 51 +++ 52 +++ 53 ++ 54 +++ 55 ++ 56 + 57 +++ 58 + 59 + 60 +++ 61 +++ 62 +++ 63 ++ 64 +++ 65 +++ 66 +++ 67 + 68 + 69 ++ 70 ++ 71 +++ 72 ++ 73 ++ 74 ++ 75 + 76 ++++ 77 +++ 78 ++ 79 ++ 80 + 81 + 82 ++ 83 ++ 84 ++ 85 +++ 86 ++++ 87 ++ 88 +++ 89 +++ 90 ++ 91 +++ 92 +++ 93 +++ 94 +++ 95 ++ 96 + 97 ++ 98 +++ 99 +++ 100 +++ 101 ++ 102 ++ 103 + 104 ++ 105 ++ 106 + 107 + 108 +++ 109 ++ 110 ++ 111 +++ 112 +++ 113 ++ 114 +++ 115 +++ 116 +++ 117 +++ 118 +++ 119 ++ 120 ++ 121 ++ 122 +++ 123 ++ 124 ++ 125 + 126 + 127 + 128 +++ 129 ++ 130 ++ 131 ++ 132 +++ 133 ++++ 134 ++ 135 +++ 136 ++ 137 +++ 138 + 139 + 140 +++ 141 ++ 142 ++++ 143 ++ 144 +++ 145 + 146 ++ 147 ++ 148 +++ 149 ++ 150 +++ 151 +++ 152 ++ 153 +++ 154 +++ 155 ++ 156 ++ 157 ++++ 158 ++ 159 ++ 160 ++ 161 ++ 162 ++ 163 ++ 164 ++ 165 + 166 + 167 ++ 168 ++ 169 +++ 170 +++ 171 ++ 172 ++ 173 ++ 174 ++ 175 ++ 176 ++ 177 ++ 178 ++ 179 ++ 180 ++ 181 ++ 182 ++ 183 ++ 184 ++ 185 ++ 186 ++ 187 + 188 + 189 + 190 ++ 191 + 192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 ++ 240 ++ 241 +++ 242 ++ 243 ++ 244 ++ 245 ++ 246 +++ 247 ++ 248 +++ 249 ++ 250 + 251 +